Aromatic sulfonyl alpha-cycloamino hydroxamic acid compounds

ABSTRACT

An aromatic sulfonyl alpha-cycloamino hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated aromatic sulfonyl alpha-cycloamino hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

This application claims the benefit of provisional application Ser. No.60/035,182 filed Mar. 4, 1997.

TECHNICAL FIELD

This invention is directed to proteinase (protease) inhibitors, and moreparticularly to aromatic sulfonyl alpha-cycloamino hydroxamic acidcompounds that, inter alia, inhibit the activity of matrixmetalloproteinases, compositions of those inhibitors, intermediates forthe syntheses of those compounds, processes for the preparation of thecompounds and processes for treating pathological conditions associatedwith pathological matrix metalloproteinase activity.

BACKGROUND OF THE INVENTION

Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals make up, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason is involved in a number of disease states.Inhibition of the enzymes responsible loss of equilibrium provides acontrol mechanism for this tissue decomposition and, therefore, atreatment for these diseases.

Degradation of connective tissue or connective tissue components iscarried out by the action of proteinase enzymes released from residenttissue cells and/or invading inflammatory or tumor cells. A major classof enzymes involved in this function are the zinc metalloproteinases(metalloproteases, or MMPs).

The metalloprotease enzymes are divided into classes with some membershaving several different names in common use. Examples are: collagenaseI (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8,neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13),stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions. Examples include rheumatoidarthritis, osteoarthritis, septic arthritis; multiple sclerosis;corneal, epidermal or gastric ulceration; tumor metastasis, invasion orangiogenesis; periodontal disease; proteinuria; Alzheimer's Disease;coronary thrombosis and bone disease. Defective injury repair processescan also occur. This can produce improper wound healing leading to weakrepairs, adhesions and scarring. These latter defects can lead todisfigurement and/or permanent disabilities as with post-surgicaladhesions.

Matrix metalloproteases are also involved in the biosynthesis of tumornecrosis factor (TNF) and inhibition of the production or action of TNFand related compounds is an important clinical disease treatmentmechanism. TNF-α, for example, is a cytokine that at present is thoughtto be produced initially as a 28 kD cell-associated molecule. It isreleased as an active, 17 kD form that can mediate a large number ofdeleterious effects in vitro and in vivo. For example, TNF can causeand/or contribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal.

TNF-α convertase is a metalloproteinase involved in the formation ofactive TNF-α. Inhibition of TNF-α convertase inhibits production ofactive TNF-α. Compounds that inhibit both MMPs activity have beendisclosed in WIPO International Publication Nos. WO 94/24140, WO94/02466 and WO 97/20824. There remains a need for effective MMP andTNF-α convertase inhibiting agents. Compounds that inhibit MMPs such ascollagenase, stromelysin and gelatinase have been shown to inhibit therelease of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan etal., Nature 376, 558-561 (1994)).

MMPs are involved in other biochemical processes in mammals as well.Included is the control of ovulation, post-partum uterine involution,possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) tothe amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI).Inhibition of these metalloproteases permits the control of fertilityand the treatment or prevention of Alzheimers Disease. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor drug or biochemical such as α₁-PI supports thetreatment and prevention of diseases such as emphysema, pulmonarydiseases, inflammatory diseases and diseases of aging such as loss ofskin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances.Treatment of cancer and/or inhibition of metastasis and/or inhibition ofangiogenesis are examples of approaches to the treatment of diseaseswherein the selective inhibition of stromelysin (MMP-3), gelatinase(MMP-2), gelatinase B (MMP-9) or collagenase III (MMP-13) are therelatively most important enzyme or enzymes to inhibit especially whencompared with collagenase I (MMP-1). A drug that does not inhibitcollagenase I can have a superior therapeutic profile. Osteoarthritis,another prevalent disease wherein it is believed that cartilagedegradation in inflamed joints is at least partially caused by MMP-13released from cells such as stimulated chrondrocytes, may be besttreated by administration of drugs one of whose modes of action isinhibition of MMP-13. See, for example, Mitchell et al., J. Clin.Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest.,97:2011-2019 (1996).

Inhibitors of metalloproteases are known. Examples include naturalbiochemicals such as tissue inhibitor of metalloproteinase (TIMP),α₂-macroglobulin and their analogs or derivatives. These are highmolecular weight protein molecules that form inactive complexes withmetalloproteases. A number of smaller peptide-like compounds thatinhibit metalloproteases have been described. Mercaptoamide peptidylderivatives have shown ACE inhibition in vitro and in vivo. Angiotensinconverting enzyme (ACE) aids in the production of angiotensin II, apotent pressor substance in mammals and inhibition of this enzyme leadsto the lowering of blood pressure.

Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are known as is shown in, for example, WO95/12389,WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMPinhibitors are disclosed in a number of published patent applicationssuch as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 thatdisclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidylback-bones or peptidomimetic back-bones, as does the article by Schwartzet al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen etal., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. NewDrugs, 15(3): 175-185 (1997).

One possible problem associated with known MMP inhibitors is that suchcompounds often exhibit the same or similar inhibitory effects againsteach of the MMP enzymes. For example, the peptidomimetic hydroxamateknown as batimastat is reported to exhibit IC₅₀ values of about 1 toabout 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, andMMP-9. Marimastat, another peptidomimetic hydroxamate was reported to beanother broad-spectrum MMP inhibitor with an enzyme inhibitory spectrumvery similar to batimastat, except that marimastat exhibited an IC₅₀value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther.,75(1): 69-75 (1997).

Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate) indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although marimastat exhibitedsome measure of efficacy via these markers, toxic side effects werenoted. The most common drug-related toxicity of marimastat in thoseclinical trials was musculoskeletal pain and stiffness, often commencingin the small joints in the hands, spreading to the arms and shoulder. Ashort dosing holiday of 1-3 weeks followed by dosage reduction permitstreatment to continue. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75(1997). It is thought that the lack of specificity of inhibitory effectamong the MMPs may be the cause of that effect.

In view of the importance of hydroxamate MMP inhibitor compounds in thetreatment of several diseases and the lack of enzyme specificityexhibited by two of the more potent drugs now in clinical trials, itwould be a great benefit if hydroxamates of greater enzyme specificitycould be found. This would be particularly the case if the hydroxamateinhibitors exhibited strong inhibitory activity against one or more ofMMP-2, MMP-9 or MMP-13 that are associated with several pathologicalconditions, while at the same time exhibiting limited inhibition ofMMP-1, an enzyme that is relatively ubiquitous and known to participatein a number of homeostatic processes. The disclosure that followsdescribes one family of hydroxamate MMP inhibitors that exhibit thosedesirable activities.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a family of molecules that amongother properties inhibit matrix metalloprotease (MMP) activity, andparticularly inhibit the activity of one or more of MMP-2, MMP-9, orMMP-13, while generally exhibiting little activity against MMP-1, aswell as to a process for treating a mammal having a condition associatedwith pathological activity.

Briefly, one embodiment of the present invention is directed to anaromatic sulfonyl alpha-cycloamino hydroxamic acid compound that can actas a matrix metalloprotease enzyme inhibitor. That compound correspondsin structure to Formula I.

wherein

m is zero, 1, 2 or 3;

n is zero, 1, or 2, and the sum of m plus n is 1, 2 or 3;

R² is hydrido, C₁-C₈ hydrocarbyl, C₁-C₆ hydrocarbyloxycarbonyl C₁-C₄hydrocarbyl, aryl C₁-C₄ hydrocarbyl, heteroaryl C₁-C₄ hydrocarbyl,aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl. R² ispreferably hydrido, C₃-C₆ cyclohydrocarbyl, t-butoxycarbonyl, phenethyl,2-propynyl, or 3-methoxybenzyl.

R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical bonded directly to the depictedSO₂-group and having a length greater than about that of a hexyl groupand less than about that of an eicosyl group. R¹ defines athree-dimensional volume, when rotated about an axis drawn through theSO₂-bonded 1-position and the 4-position of a 6-membered ring radical ordrawn through the SO₂-bonded 1-position and the center of 3,4-bond of a5-membered ring radical, whose widest dimension in a directiontransverse to the axis of rotation is about that of one furanyl ring toabout that of two phenyl rings.

R¹ preferably contains a single aromatic or heteroaromatic ring that isitself substituted with another substituent, R³. R¹ most preferablycontains a phenyl ring, Ph, that itself has a substituent, R³, at the4-position. R³ is preferably a phenyl, a phenoxy, a phenylazo, athiophenoxy, an anilino, a benzamido, a nicotinamido, anisonicotinamido, a picolinamido or a phenylureido group that can itselfbe substituted at the meta- or para-position or both by a single atom ora substituent containing a longest chain of up to eight atoms, excludinghydrogen.

Particularly preferred compounds correspond in structure to Formulas IIand IV, below, wherein R¹ and R² are as before described.

Most preferably, a contemplated compound contains an R¹ substituent thatis PhR³, wherein Ph is phenyl, R³ is bonded at the 4-position and issubstituent having a chain length of 3 to about 14 carbon atoms such asa hydrocarbyl or hydrocarbyloxy group [e.g., C₃-C₁₄ hydrocarbyl or—O—C₂-C₁₄ hydrocarbyl], a phenyl group, a phenoxy group, a thiophenoxygroup, an anilino group, a phenylazo group, an phenylureido group, abenzamido group, a nicotinamido group, an isonicotinamido group, or apicolinamido group.

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a compound described hereinbefore in anenzyme-inhibiting effective amount to a mammalian host having such acondition. The use of repeated administrations is particularlycontemplated.

Among the several benefits and advantages of the present invention arethe provision of compounds and compositions effective as inhibitors ofmatrix metalloproteinase activity, and the provision of such compoundsand compositions that are effective for the inhibition ofmetalloproteinases implicated in diseases and disorders involvinguncontrolled breakdown of connective tissue.

More particularly, a benefit of this invention is the provision of acompound and composition effective for inhibiting metalloproteinases,particularly MMP-13 and/or MMP-2, associated with pathologicalconditions such as, for example, rheumatoid arthritis, osteoarthritis,or septic arthritis; corneal, epidermal or gastric ulceration; tumormetastasis, invasion or angiogenesis; periodontal disease; proteinuria;multiple sclerosis Alzheimer's Disease, coronary thrombosis and bonedisease.

An advantage of the invention is the provision of a method for preparingsuch compositions. Another benefit is the provision of a method fortreating a pathological condition associated with abnormal matrixmetalloproteinase activity.

Another advantage of the invention is the provision of compounds,compositions and methods effective for treating such pathologicalconditions by selective inhibition of a metalloproteinase such as MMP-13and MMP-2 associated with such conditions with minimal side effectsresulting from inhibition of other proteinases such as MMP-1, whoseactivity is necessary or desirable for normal body function.

Still further benefits and advantages of the invention will be apparentto the skilled worker from the disclosure that follows.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

In accordance with the present invention, it has been found that certainaromatic sulfonyl alpha-cycloamino hydroxamic acids (hydroxamates) areeffective for inhibition of matrix metalloproteinases (“MMPs”) believedto be associated with uncontrolled or otherwise pathological breakdownof connective tissue. In particular, it has been found that thesecertain aromatic sulfonyl alpha-cycloamino hydroxamic acids areeffective for inhibition of collagenase III (MMP-13) and also gelatinaseA (MMP-2), which can be particularly destructive to tissue if present orgenerated in abnormal quantities or concentrations, and thus exhibit apathological activity. Moreover, it has been discovered that many ofthese aromatic sulfonyl alpha-cycloamino hydroxamic acids are selectivein the inhibition of MMP-13, as well as other MMPs associated withdiseased conditions without excessive inhibition of other collagenasesessential to normal bodily function such as tissue turnover and repair.More particularly, it has been found that particularly preferred thearomatic sulfonyl alpha-cycloamino hydroxamic acids are particularlyactive in inhibiting of MMP-13 and MMP-2, while having a limited orminimal effect on MMP-1. This point is discussed in detail hereinafterand is illustrated in the Inhibition Table (Table 13) hereinafter.

One embodiment of the present invention is directed to an aromaticsulfonyl alpha-cycloamino hydroxamic acid compound that can act as amatrix metalloprotease enzyme inhibitor. That compound corresponds instructure to Formula I.

wherein

m is zero, 1, 2 or 3;

n is zero, 1, or 2, and the sum of m plus n is 1, 2 or 3;

R² is hydrido, C₁-C₈ hydrocarbyl, C₁-C₆ hydrocarbyloxycarbonyl C₁-C₄hydrocarbyl, aryl C₁-C₄ hydrocarbyl, heteroaryl C₁-C₄ hydrocarbyl,aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl. R² ispreferably hydrido, C₃-C₆ cyclohydrocarbyl, t-butoxycarbonyl, phenethyl,2-propynyl, or 3-methoxybenzyl; and

R¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical bonded directly to the depictedSO₂-group and having a length equivalent to a length that is greaterthan about that of a fully extended hexyl group and less than about thatof a fully extended eicosyl group, said R¹ defining a three-dimensionalvolume, when rotated about an axis drawn through the SO₂-bonded1-position and the 4-position of a 6-membered ring radical or drawnthrough the SO₂-bonded 1-position and the center of 3,4-bond of a5-membered ring radical, whose widest dimension in a directiontransverse to the axis of rotation is about that of one furanyl ring toabout that of two phenyl rings.

As noted above, an R¹ substituent contains a 5- or 6-memberedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bondeddirectly to the depicted SO₂-group. An R¹ substituent also has length,width and substitution requirements that are discussed in detail below.It is noted here, however, that a single-ringed or fused ringcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is not itselflong enough to fulfill the length requirement. As such, thatcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical must itself besubstituted.

Exemplary 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl orheteroaryl radicals that can constitute a portion of a R¹ substituentand are themselves substituted as discussed herein include phenyl, 2-,3-, or 4-pyridyl, 2-naththyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or3-benzo(b)thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3-pyrrolyl,2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or3-pyrazolidinyl and the like. A phenyl radical is particularly preferredand is used illustratively herein.

When examined along its longest chain of atoms, an R¹ substituent,including its own substituent when present, has a total length that isgreater than the corresponding length of a fully extended saturatedchain of six carbon atoms (a hexyl group); i.e., a length of a heptylchain or longer, and a length that is less than that of a fully extendedsaturated chain of about 20 carbons (an eicosyl group). Preferably, thatlength is equivalent to the length of a fully extended saturated chainof about 8 to about 18 carbon atoms, even though many more atoms may bepresent in ring structures or substituents. This length requirement isdiscussed further below.

Looked at more generally, and aside from specific moieties from which itis constructed, an R¹ substituent (radical, group or moiety) has alength equivalent to that of a fully extended heptyl group or greater.Such an R¹ substituent also has a length that is equivalent to less thanthat of a fully extended eicosyl group. That is to say that a R¹ is asubstituent having a length greater than that of a saturated six carbonchain and shorter than that of a saturated twenty carbon chain, and morepreferably, a length greater than that of an octyl group and less thanthat of a palmityl group. The radical chain lengths are measured alongthe longest linear atom chain in the radical, following the skeletalatoms of a ring where necessary. Each atom in the chain, e.g. carbon,oxygen or nitrogen, is presumed to be carbon for ease in calculation.

Such lengths can be readily determined by using published bond angles,bond lengths and atomic radii, as needed, to draw and measure a chain,or by building models using commercially available kits whose bondangles, lengths and atomic radii are in accord with accepted, publishedvalues. Radical (substituent) lengths can also be determined somewhatless exactly by presuming, as is done here, that all atoms have bondlengths of saturated carbon, that unsaturated and aromatic bonds havethe same lengths as saturated bonds and that bond angles for unsaturatedbonds are the same as those for saturated bonds, although theabove-mentioned modes of measurement are preferred. For example, a4-phenyl or 4-pyridyl group has a length of a four carbon chain, as doesa propoxy group, whereas a biphenyl group has a length of about an eightcarbon chain using a contemplated measurement mode.

In addition, an R¹ substituent, when rotated about an axis drawn throughthe SO₂-bonded 1-position and the 4-position of a 6-membered ringradical or the SO₂-bonded 1-position and through the 3,4 bond of a5-membered ring radical defines a three-dimensional volume whose widestdimension has the width equivalent to from about one furanyl ring toabout the width of two phenyl rings in a direction transverse to thataxis of rotation.

When utilizing this width or volume criterion, a fused ring system suchas a naphthyl or purinyl radical is considered to be a 6- or 5-memberedring that is substituted at appropriate positions numbered from theSO₂-linkage that is deemed to be at the 1-position as discussed before.Thus, a 2-naphthyl substituent or an 8-purinyl substituent is anappropriately sized R¹ radical as to width when examined using the aboverotational width criterion. On the other hand, a 1-naphthyl group or a7- or 9-purinyl group is too large upon rotation and is excluded.

As a consequence of these length and width requirements, R¹ substituentssuch as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)phenyl,4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl],4-(phenylazo)phenyl, 4-(phenylureido)phenyl, 4-(anilino)phenyl,4-(nicotinamido)phenyl, 4-(isonicotinamido)phenyl,4-(picolinamido)phenyl and 4-(benzamido)phenyl are among particularlypreferred R¹ substituents, with 4-(phenoxy)phenyl and4-(thiophenyl)phenyl being most preferred.

An SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicalis a 5- or 6-membered single-ring that is itself substituted with oneother substituent, R³. The SO₂-linked single-ringed cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is R³-substituted at its own4-position when a 6-membered ring and at its own 3-position when a5-membered ring. The cyclohydrocarbyl, heterocyclo, aryl or heteroarylradical to which R³ is bonded is preferably a phenyl group, so that R¹is preferably PhR³ in which R³ is bonded at the 4-position of theSO₂-linked phenyl (Ph) radical, and in which R³ can itself be optionallysubstituted as is discussed hereinafter. Substitution at the 2-positionof a SO₂-linked cyclohydrocarbyl, heterocyclo, aryl or heteroarylradical appears to greatly lessen inhibitory potency toward MMP enzymes,and is absent from a contemplated compound.

A contemplated R³ substituent can be a single-ringed cyclohydrocarbyl,heterocyclo, aryl or heteroaryl group or another substituent having achain length of 3 to about 14 carbon atoms such as a hydrocarbyl orhydrocarbyloxy group [e.g., C₃-C₁₄ hydrocarbyl or O—C₂-C₁₄ hydrocarbyl],a phenyl group, a phenoxy group [—OC₆H₅], a thiophenoxy group[phenylsulfanyl; —SC₆H₅], an anilino group [—NHC₆H₅], a phenylazo group[—N₂C₆H₅], a phenylureido group [aniline carbonylamino; —NHC(O)NH—C₆H₅],a benzamido group [—NHC(O)C₆H₅], a nicotinamido group [3-NHC(O)C₅H₄N],an isonicotinamido group [4-NHC(O)C₅H₄N], or a picolinamido group[2-NHC(O)C₅H₄N]. As noted before in conjunction with the discussion ofR¹, most preferred R³ substituents are phenoxy and thiophenoxy groupsthat are preferably themselves free of substitution. Additionallycontemplated R³ substituent groups include a heterocyclo,heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl,heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl,arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl,hydrocarboylhydrocarbyl, arylhydrocarboylhydrocarbyl,arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl,hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl,heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl,arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl,arylhydrocarbylamino, heteroarylhydrocarbylamino, or a heteroarylthiogroup.

A contemplated R³ substituent can itself also be substituted with one ormore substituent radicals at the meta- or para-position or both of asix-membered ring with a single atom or a substituent containing alongest chain of up to ten atoms, excluding hydrogen. Exemplarysubstituent radicals include a halo, hydrocarbyl, hydrocarbyloxy, nitro,cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy,mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino,arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino,heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl,heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio,heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio,cyclohydrocarbylamino, heteroarylhydrocarbyloxy,heteroarylhydrocarbylthio, heteroarylhydrocarbylamino,arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino,heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy,alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl,hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl,hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio,hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbyl,hydrocarbylhydroxycarbonylhydrocarbylthio,hydrocarbyloxycarbonylhydrocarbyloxy,hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino,arylcarbonylamino, cyclohydrocarbylcarbonylamino,heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino,heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino,arylhydrocarbylsulfonylamino, heteroarylsulfonylamino,heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino,heterocyclohydrocarbylsulfonylamino and N-monosubstituted orN,N-disubstituted aminohydrocarbyl group wherein the substituent(s) onthe nitrogen are selected from the group consisting of hydrocarbyl,aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl,hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the nitrogen andtwo substituents attached thereto form a 5- to 8-membered heterocyclicor heteroaryl ring group.

Thus, initial studies indicate that so long as the length, substitutionand width (volume upon rotation) requirements of an SO₂-linked R¹substituent discussed herein are met, an R¹ substituent can be extremelyvaried.

A particularly preferred R³ substituent of an SO₂-linked Ph group is asingle-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo,phenylureido, nicotinamido, isonicotinamido, picolinamido, anilino orbenzamido group that is unsubstituted or is itself substituted(optionally substituted) at the para-position when a 6-membered ring orthe 3-position when a 5-membered ring. Here, single atoms such ashalogen moieties or substituents that contain one to a chain of aboutten atoms other than hydrogen such as C₁-C₁₀ hydrocarbyl, C₁-C₉hydrocarbyloxy or carboxyethyl groups can be used.

Exemplary particularly preferred substituted PhR³ (particularlypreferred substituted R¹) substituents include biphenyl,4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-phenylureido,4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido, and 4-picolinamido.Exemplary particularly preferred R³ groups contain a 6-membered aromaticring and include a phenyl group, a phenoxy group, a thiophenoxy group, aphenylazo group, a phenylureido group, an anilino group, a nicotinamidogroup, an isonicotinamido group, a picolinamido group and a benzamidogroup.

More specifically, a particularly preferred sulfonyl butanhydroxamatecompound has an R³ substituent that is a phenyl group, a phenoxy group,a thiophenoxy group, a phenylazo group, a phenylureido group, an anilinogroup, a nicotinamido group, an isonicotinamido group, a picolinamidogroup or a benzamido group that is itself optionally substituted at itsown meta or para-position or both with a moiety that is selected fromthe group consisting of a halogen, a C₁-C₉ hydrocarbyloxy (—O—C₁-C₉hydrocarbyl) group, a C₁-C₁₀ hydrocarbyl group, a di-C₁-C₉hydrocarbylamino [—N(C₁-C₉ hydrocarbyl)(C₁-C₉ hydrocarbyl)] group, acarboxyl C₁-C₈ hydrocarbyl (C₁-C₈ hydrocarbyl-CO₂H) group, a C₁-C₄hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl [C₁-C₄hydrocarbyl-O—(CO)—C₁-C₄ hydrocarbyl] group, a C₁-C₄hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl [C₁-C₄ hydrocarbyl(CO)—O—C₁-C₄hydrocarbyl] group and a C₁-C₈ hydrocarbyl carboxamido [—NH(CO)—C₁-C₈hydrocarbyl] group, or is substituted at the meta- and para-positions bytwo methyl groups or by a C₁-C₂ alkylenedioxy group such as amethylenedioxy group.

Inasmuch as a contemplated SO₂-linked cyclohydrocarbyl, heterocyclo,aryl or heteroaryl radical is itself preferably substituted with a6-membered aromatic ring, two nomenclature systems are used togetherherein for ease in understanding substituent positions. The first systemuses position numbers for the ring directly bonded to the SO₂-group,whereas the second system uses ortho, meta or para for the position ofone or more substituents of a 6-membered ring bonded to a SO₂-linkedcyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. When an R³substituent is other than a 6-membered ring, substituent positions arenumbered from the position of linkage to the aromatic or heteroaromaticring. Formal chemical nomenclature is used in naming particularcompounds.

Thus, the 1-position of an above-discussed SO₂-linked cyclohydrocarbyl,heterocyclo, aryl or heteroaryl radical is the position at which theSO₂-group is bonded to the ring. The 4- and 3-positions of ringsdiscussed here are numbered from the sites of substituent bonding fromthe SO₂-linkage as compared to formalized ring numbering positions usedin heteroaryl nomenclature.

In particularly preferred practice, the alpha-cycloamino substituent isa 4-piperidinyl group, and a contemplated compound has a structure thatcorresponds to Formula II, below, wherein R² and R¹ are as beforedefined.

As noted before, it is also particularly preferred that R¹ contain aphenyl group (Ph) linked at its own 4-position to another substituent,R³, so that R¹ is PhR³. A most preferred compound has a structure thatcorresponds to Formula III, below, wherein R² and R³ are as definedbefore.

Yet another preferred compound corresponds in structure to a compound ofFormula IV, below, wherein R² and R¹ are as defined before. Again, R¹ isPhR³ in particularly preferred practice, wherein PhR³ is as definedbefore.

The length of a R¹ substituent bonded to the SO₂ group is believed toplay a role in the overall activity of a contemplated inhibitor compoundagainst MMP enzymes generally. Thus, a compound having an R¹ substituentthat is shorter in length than an octyl group, e.g., a 4-methoxyphenylgroup, typically exhibits moderate to poor inhibitory activity againstall of the MMP enzymes, whereas compounds whose R¹ substituents have alength of about an octyl chain or longer, e.g., a 4-phenoxyphenyl groupthat has a length of about a nine-carbon chain, typically exhibit goodto excellent potencies against MMP-13 or MMP-2 and also selectivityagainst MMP-1. Exemplary data for some of those latter compounds areprovided in Table 13 hereinafter.

The identity of the R¹ substituent group can also play a role in theactivity of a compound as an inhibitor of particular MMP enzymes. Forexample, the compound of Example 1,N-hydroxy-4-[[[4-(benzoylamino)phenyl]sulfonyl]methyl]-4-piperidinecarboxamide,monohydrochloride, whose SO₂-bonded aryl group is a phenyl substituentbonded to a benzamido moiety is virtually unbound by MMP-1, whileexhibiting excellent activity against MMP-2 and moderate activityagainst MMP-13. These comparative activities can be seen in Table 13hereinafter.

The word “hydrocarbyl” is used herein as a short hand term to includestraight and branched chain aliphatic as well as alicyclic groups orradicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl andalkynyl groups are contemplated, whereas aromatic hydrocarbons such asphenyl and naphthyl groups, which strictly speaking are also hydrocarbylgroups, are referred to herein as aryl groups or radicals, as discussedhereinafter. Where a specific aliphatic hydrocarbyl substituent group isintended, that group is recited; i.e., C₁-C₄ alkyl, methyl or dodecenyl.Exemplary hydrocarbyl groups contain a chain of 1 to about 12 carbonatoms, and preferably one to about 10 carbon atoms. A particularlypreferred hydrocarbyl group is an alkyl group.

Usual chemical suffix nomenclature is followed when using the word“hydrocarbyl” except that the usual practice of removing the terminal“yl” and adding an appropriate suffix is not always followed because ofthe possible similarity of a resulting name to one or more substituents.Thus, a hydrocarbyl ether is referred to as a “hydrocarbyloxy” grouprather than a “hydrocarboxy” group as may possibly be more proper whenfollowing the usual rules of chemical nomenclature. On the other hand, ahydrocarbyl group containing a —C(O)O— functionality is referred to as ahydrocarboyl group inasmuch as there is no ambiguity in using thatsuffix. As a skilled worker will understand, a substituent that cannotexist such as a C₁ alkenyl group is not intended to be encompassed bythe word “hydrocarbyl”.

As stated before, a particularly preferred hydrocarbyl group is an alkylgroup. As a consequence, a generalized, but more preferred substituentcan be recited by replacing the descriptor “hydrocarbyl” with “alkyl” inany of the substituent groups enumerated herein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyland the like. Examples of suitable alkenyl radicals include ethenyl(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples ofalkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

The term “carbonyl”, alone or in combination, means a —C(═O)— groupwherein the remaining two bonds (valences) are independentlysubstituted. The term “thiol” or “sulfhydryl”, alone or in combination,means a —SH group. The term “thio” or “thia”, alone or in combination,means a thiaether group; i.e., an ether group wherein the ether oxygenis replaced by a sulfur atom.

The term “amino”, alone or in combination, means an amine or —NH₂ group,whereas the term mono-substituted amino, alone or in combination, meansa substituted amine —N(H) (substituent) group wherein one hydrogen atomis replaced with a substituent, and disubstituted amine means a—N(substituent)₂ wherein two hydrogen atoms of the amino group arereplaced with independently selected substituent groups. Amines, aminogroups and amides are classes that can be designated as primary (I°),secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted ordi-substituted depending on the degree of substitution of the aminonitrogen. Quaternary amine (IV°) means a nitrogen with four substituents(—N⁺ (substituent)₄) that is positively charged and accompanied by acounter ion or N-oxide means one substituent is oxygen and the group isrepresented as (—N⁺ (substituent)₃—O⁻); i.e., the charges are internallycompensated.

The term “cyano”, alone or in combination, means a —C-triple bond-N(—CN)group. The term “azido”, alone or in combination, means a —N-doublebond-N-double bond-N (—N═N═N) group.

The term “hydroxyl”, alone or in combination, means a —OH group. Theterm “nitro”, alone or in combination, means a —NO₂ group.

The term “azo”, alone or in combination, means a —N═N— group wherein thebonds at the terminal positions are independently substituted. The term“hydrazino”, alone or in combination, means a —NH—NH— group wherein theremaining two bonds (valences) are independently substituted. Thehydrogen atoms of the hydrazino group can be replaced, independently,with substituents and the nitrogen atoms can form acid addition salts orbe quaternized.

The term “sulfonyl”, alone or in combination, means a —S(═O)₂— groupwherein the remaining two bonds (valences) can be independentlysubstituted. The term “sulfoxido”, alone or in combination, means a—S(═O)₁— group wherein the remaining two bonds (valences) can beindependently substituted. The term “sulfonylamide”, alone or incombination, means a —S(═O)₂—N═ group wherein the remaining three bonds(valences) are independently substituted. The term “sulfinamido”, aloneor in combination, means a —S(═O)₁N═ group wherein the remaining threebonds (valences) are independently substituted. The term “sulfenamide”,alone or in combination, means a —S—N═ group wherein the remaining threebonds (valences) are independently substituted.

The term “hydrocarbyloxy”, alone or in combination, means a hydrocarbylether radical wherein the term hydrocarbyl is as defined above. Examplesof suitable hydrocarbyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, allyloxy, n-butoxy, iso-butoxy, sec-butoxy,tert-butoxy and the like. The term “cyclohydrocarbyl”, alone or incombination, means a hydrocarbyl radical that contains 3 to about 8carbon atoms, preferably from about 3 to about 6 carbon atoms, and iscyclic. Examples of such cyclohydrocarbyl radicals include cyclopropyl,cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctynyl and the like. Theterm “cyclohydrocarbylhydrocarbyl” means an hydrocarbyl radical asdefined above which is substituted by a cyclohydrocarbyl as also definedabove.

The term “aryl”, alone or in combination, means a phenyl or naphthylradical that optionally carries one or more substituents selected fromhydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro and thelike, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, and the like. The term“arylhydrocarbyl”, alone or in combination, means an hydrocarbyl radicalas defined above in which one hydrogen atom is replaced by an arylradical as defined above, such as benzyl, 2-phenylethyl and the like.The term “arylhydrocarbyloxycarbonyl”, alone or in combination, means aradical of the formula —C(O)—O— arylhydrocarbyl in which the term“arylhydrocarbyl” has the significance given above. An example of anarylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term“aryloxy” means a radical of the formula aryl-O— in which the term arylhas the significance given above. The term “aromatic ring” incombinations such as substituted-aromatic ring sulfonamide,substituted-aromatic ring sulfinamide or substituted-aromatic ringsulfenamide means aryl or heteroaryl as defined above.

The terms “hydrocarbyloyl” or “hydrocarbylcarbonyl”, alone or incombination, mean an acyl radical derived from an hydrocarbylcarboxylicacid, examples of which include acetyl, propionyl, acryloyl, butyryl,valeryl, 4-methylvaleryl, and the like. The term“cyclohydrocarbylcarbonyl” means an acyl group derived from a monocyclicor bridged cyclohydrocarbylcarboxylic acid such as cyclopropanecarbonyl,cyclohexenecarbonyl, adamantanecarbonyl, and the like, or from abenz-fused monocyclic cyclohydrocarbylcarboxylic acid that is optionallysubstituted by, for example, a hydrocarbyloylamino group, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms“arylhydrocarbyloyl” or “arylhydrocarbylcarbonyl” mean an acyl radicalderived from an aryl-substituted hydrocarbylcarboxylic acid such asphenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminocinnamoyl,4-methoxycinnamoyl and the like.

The terms “aroyl” or “arylcarbonyl” means an acyl radical derived froman aromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

The heterocyclyl (heterocyclo) or heterocyclohydrocarbyl portion of aheterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylhydrocarbyloxycarbonyl, or heterocyclohydrocarbyl group orthe like is a saturated or partially unsaturated monocyclic, bicyclic ortricyclic heterocycle that contains one to four hetero atoms selectedfrom nitrogen, oxygen and sulphur, which is optionally substituted onone or more carbon atoms by a halogen, alkyl, alkoxy, oxo group, and thelike, and/or on a secondary nitrogen atom (i.e., —NH—) by anhydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloyl, aryl orarylhydrocarbyl or on a tertiary nitrogen atom (i.e. ═N—) by oxido andthat is attached via a carbon atom. The tertiary nitrogen atom withthree substituents can also form a N-oxide [═N(O)—] group. Examples ofsuch heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, and the like.

The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or aheteroarylhydrocarbyloyl (heteroarylhydrocarbyl carbonyl) group or thelike is an aromatic monocyclic, bicyclic, or tricyclic heterocycle thatcontains the hetero atoms and is optionally substituted as defined abovewith respect to the definition of heterocyclyl. A “heteroaryl” group isan aromatic heterocyclic ring substituent that can contain one, two,three or four atoms in the ring that are other than carbon. Thoseheteroatoms can be nitrogen, sulfur or oxygen. A heteroaryl group cancontain a single five- or 6-membered ring or a fused ring system thatcontains two 6-membered rings or a five- and a 6-membered ring.Exemplary heteroaryl groups include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ringsubstituents such as 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups;six/five-membered fused ring substituents such as benzothiofuranyl,isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl andanthranilyl groups; and six/six-membered fused rings such as 1,2-, 1,4-,2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, and 1,4-enzoxazinyl groups.

The term “cyclohydrocarbylhydrocarbyloxycarbonyl” means an acyl groupderived from a cyclohydrocarbylhydrocarbyloxycarboxylic acid of theformula cyclohydrocarbylhydrocarbyl-O—COOH whereincyclohydrocarbylhydrocarbyl has the significance given above. The term“aryloxyhydrocarbyloyl” means an acyl radical of the formulaaryl-O-hydrocarbyloyl wherein aryl and hydrocarbyloyl have thesignificance given above. The term “heterocyclyloxycarbonyl”, means anacyl group derived from heterocyclyl-O—COOH wherein heterocyclyl is asdefined above. The term “heterocyclylhydrocarbyloyl” is an acyl radicalderived from a heterocyclyl-substituted hydrocarbylcarboxylic acidwherein heterocyclyl has the significance given above. The term“heterocyclylhydrocarbyloxycarbonyl” means an acyl radical derived froma heterocyclyl-substituted hydrocarbyl-O—COOH wherein heterocyclyl hasthe significance given above. The term “heteroaryloxycarbonyl” means anacyl radical derived from a carboxylic acid represented byheteroaryl-O—COOH wherein heteroaryl has the significance given above.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from hydrogen, hydrocarbyl, aryl, aralkyl, cyclohydrocarbyl,cyclohydrocarbylhydrocarbyl radicals and the like. The term“aminohydrocarbyloyl” means an acyl group derived from anamino-substituted hydrocarbylcarboxylic acid wherein the amino group canbe a primary, secondary or tertiary amino group containing substituentsindependently selected from hydrogen, alkyl, aryl, aralkyl,cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine. The term“halohydrocarbyl” means a hydrocarbyl radical having the significance asdefined above wherein one or more hydrogens are replaced with a halogen.Examples of such halohydrocarbyl radicals include chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,1,1,1-trifluoroethyl and the like. The term perfluorohydrocarbyl means ahydrocarbyl group wherein each hydrogen has been replaced by a fluorineatom. Examples of such perfluorohydrocarbyl groups, in addition totrifluoromethyl above, are perfluorobutyl, perfluoroisopropyl,perfluorododecyl and perfluorodecyl.

Table 1 through Table 12, below, show several contemplated aromaticsulfonyl alpha-cycloamino hydroxamic acid compounds as structuralformulas that illustrate substituent groups. Each group of compounds isillustrated by a generic formula, followed by a series of preferredmoieties or groups that constitute various substituents that can beattached at the position clearly shown in the generic structure. Thesubstituent symbols, e.g., R¹ and R², are as shown in each Table. Onebond (straight line) is shown with those substituents to indicate therespective positions of attachment in the illustrated compound. Thissystem is well known in the chemical communication arts and is widelyused in scientific papers and presentations.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

TABLE 10

TABLE 11

TABLE 12

—SO₂—CH₃

Treatment Process

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a compound described hereinbefore in anMMP enzyme-inhibiting effective mount to a mammalian host having such acondition. The use of administration repeated a plurality of times isparticularly contemplated.

A contemplated compound is used for treating a host mammal such as amouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee orhuman that has a condition associated with pathological matrixmetalloprotease activity.

Also contemplated is the similar use of a contemplated compound in thetreatment of a disease state that can be affected by the activity ofmetalloproteases such as TNF-α convertase. Exemplary of such diseasestates are the acute phase responses of shock and sepsis, coagulationresponses, hemorrhage and cardiovascular effects, fever andinflammation, anorexia and cachexia.

In treating a disease condition associated with pathological matrixmetalloproteinase activity, a contemplated MMP inhibitor compound can beused, where appropriate, in the form of an amine salt derived from aninorganic or organic acid. Exemplary acid salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate.

Also, a basic nitrogen-containing group can be quaternized with suchagents as lower alkyl (C₁-C₆) halides, such as methyl, ethyl, propyl,and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C₈-C₂₀)halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromidesand iodides, aralkyl halides like benzyl and phenethyl bromides, andothers to provide enhanced water-solubility. Water or oil-soluble ordispersible products are thereby obtained as desired. The salts areformed by combining the basic compounds with the desired acid. Othercompounds useful in this invention that are acids can also form salts.Examples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases orbasic quaternary ammonium salts.

In some cases, the salts can also be used as an aid in the isolation,purification or resolution of the compounds of this invention.

Total daily dose administered to a host mammal in single or divideddoses of an MMP enzyme-inhibiting effective amount can be in amounts,for example, of about 0.001 to about 100 mg/kg body weight daily,preferably 0.001 to about 30 mg/kg body weight daily and more usuallyabout 0.01 to about 10 mg. Dosage unit compositions can contain suchamounts or submultiples thereof to make up the daily dose. A suitabledose can be administered, in multiple sub-doses per day. Multiple dosesper day can also increase the total daily dose, should such dosing bedesired by the person prescribing the drug.

The dosage regimen for treating a disease condition with a compoundand/or composition of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed can vary widely and thereforecan deviate from the preferred dosage regimen set forth above.

A compound useful in the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.(Easton, Pa.: 1975) and Liberman, H. A. and Lachman, L., eds.,Pharmaceutical Dosage Forms, Marcel Decker (New York, N.Y.: 1980).

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compounds can be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets can contain a controlled-release formulation as canbe provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formscan also comprise buffering agents such as sodium citrate, magnesium orcalcium carbonate or bicarbonate. Tablets and pills can additionally beprepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds can be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

Preparation of Useful Compounds

Schemes A and 1A through 2C hereinbelow illustrate chemical processesand transformations that can be useful for the preparation of compoundsuseful in this invention; i.e., compounds of Formulas I-IV, withparticular emphasis on compounds of Formulas II and III, and similarcompounds.

The generic Scheme A shows the conversion of an amino acid, which can beprotected or unprotected, into a compound of this invention. Thecarboxylic acid can be protected with a group P such as an alkyl estersuch as methyl, ethyl, tert-butyl, tetrahydropyranyl and the like or anarylalkyl ester such as benzyl or it can remain as a carboxylic acid;i.e., where P is —OH.

A protected amino acid such as an ethyl ester is preferred. The groupsR² and R¹ are as defined before including hydrogen, tert-butoxycarbonyl(BOC or tBOC), benzyloxycarbonyl (Z) and iso-butyloxycarbonyl. The aminecan be considered as being a protected intermediate as well as being acontemplated compound when R² is other than hydrogen. The parameters mand n are also as defined before. The leaving group, X, can be a halogensuch as chlorine, bromine or iodine or an active ester such as asulfonate ester, e.g., toluenesulfonate (tosylate), triflate, mesylateand the like.

The cyclic amino acids used to prepare the compounds of this inventioncan be prepared in ways known to those skilled in the art. Reduction ofheteroaryl or unsaturated or partially unsaturated heterocycles can becarried out. For example, the six membered ring compounds can besynthesized by reduction of the corresponding 2-, 3- or 4-pyridinecarboxylic acids, 2-, or 3-pyrazole carboxylic acids or derivativesthereof. The reduction can by hydrogenation in the presence of acatalyst or hydride reduction using a hydride transfer agent such aslithium aluminum hydride.

Exemplary starting amino acids or their derivatives, include ethylisonipecotate, ethyl nipecotate, pipecolinic acid, proline or itsisomers, pyroglutamate or its isomers. The R, S and RS isomers of theamino acids can be used. Some starting material can be obtained fromcommercial sources. A preferred starting material is ethyl isonipecotatethat is used illustratively hereinafter.

Alkylation of the aminoacid at the carbon alpha to the carbonyl group toform contemplated compound precursors can be carried out by firstforming an anion using a base. Bases are discussed below. The preferredbases are strong bases that are either hindered and/or non-nucleophilicsuch as lithium amides, metal hydrides or lithium alkyls. A preferredbase is lithium diisopropylamide (LDA) in a dipolar aprotic solvent orTHF.

Following or during formation of the anion, an alkylating agent (anelectrophile) is added which undergoes a nucleophilic substitutionreaction. Non-limiting examples of such alkylating agents are 1,1-,1,2-dihaloalkanes or haloalkanes also substituted by an activated estergroup. Activated ester groups are well known in the art and can include,for example, an ester of a 1,2-halo-alcohol such as a bromo-, iodo- orchloro-ethane para-toluene sulfonate, triflate or mesylate. Preferredalkylating agents are diiodomethane or 1-bromo-2-chloroethane.

Room temperature or less or moderate warming (−10° C. to 60° C.) are thepreferred temperatures for carrying out the alkylation reaction. Ifdesired, the reaction temperature might be about −68° C. to the refluxpoint of the reaction solvent or solvents. The preferred solvent for analkylation reaction is tetrahydrofuran (THF).

Acids are used in many reactions during various synthesis. The Schemesas well as this discussion preparative methods illustrate acid use forthe removal of the THP protecting group to produce a hydroxamic acid,removal of a tert-butoxy carbonyl group, hydroxylamine/ester exchangeand the like. These methods, as is well known in the art, can use acidor acid catalysts. The acid can be mono-, di- or tri-protic organic orinorganic acids. Examples of acids include hydrochloric acid, phosphoricacid, sulfuric acid, acetic acid, formic acid, citric acid, succinicacid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorousacid, p-toluene sulfonic acid, trifluoromethane sulfonic acid,trifluoroacetic acid, difluoroacetic acid, benzoic acid, methanesulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid,trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid,trinitrobenzoic acid, and the like. They can also be Lewis acids such asaluminum chloride, borontrifluoride, antimony pentafluoride and thelike.

The nitrogen substituent R² on the amino acid portion of thecontemplated compounds can be varied. In addition, that variation can beaccomplished at different stages in the synthetic sequence based on theneeds and objectives of the skilled person preparing the compounds ofthis invention.

The N-side chain variations can include replacing the hydrogensubstituent with an alkyl, arylalkyl, alkene or alkyne group. Thatalkylation can be accomplished by methods well known in the art such asalkylation of the amine with an electrophile such as halo- or sulfateester (activated ester) derivative of the desired side chain, and isgenerally carried out in the presence of a base such as those discussedabove, using a pure or mixed solvent as discussed above. A preferredbase is postassium carbonate and a preferred solvent is DMF.

The resulting alkenes and alkynes can be reduced, if desired, byhydrogenation with a metal catalyst and hydrogen, to an alkyl orarylalkyl compound. The alkyne or arylalkyne compound can be similarlyreduced to a alkene or alkane under catalytic hydrogenation conditionsas discussed above or with an deactivated metal catalyst. Catalysts caninclude, for example, Pd, Pd on Carbon, Pt, PtO₂ and the like. Lessrobust catalysts include such thing as Pd on BaCO₃ or Pd with quinolineor/and sulfur.

An alternative method for alkylation of the amine nitrogen is reductivealkylation. This process, well known in the art, allows treatment of thesecondary amine with an aldehyde or ketone in the presence of a reducingagent such as borane, borane:THF, borane:pyridine, lithium aluminumhydride. Alternatively, reductive alkylation can be carried outhydrogenation conditions in the presence of a metal catalyst. Catalysts,hydrogen pressures and temperatures are discussed above and are wellknown in the art. A preferred reductive alkylation catalyst isborane:pyridine complex.

A contemplated compound includes those wherein R² as listed aboveprovides amino acid carbamates. Non-limiting examples of thesecarbamates are the carbobenzoxycarbonyl (Z, CBZ, benzyloxycarbonyl),isobytoxycarbonyl and tert-butoxycarbonyl (BOC, t-BOC) compounds. Thematerials can be made, as discussed above, at various stages in thesynthesis based on the needs and decisions made by a person skilled inthe art using methods well known in the art. Useful synthetic techniquesand reagents include those used in protein, peptide and amino acidsynthesis, coupling and transformation chemistry. The use of thetert-butoxycarbonyl (BOC) and benzyloxycarbonyl (Z) as well as theirsynthesis and removal are examples of such protection or synthesisschemes.

Transformations of amino acids, amino esters, amino acid hydroxamates,amino acid hydroxamate derivatives and amino acid amides to contemplatedcompounds is shown in the schemes. Exemplary transformations include,for example, active ester or mixed anhydride couplings wherein preferredbases, if required, are tertiary amines such as N-methylmorpholine.Reagents for protection of the amine group of the protected amino acidsinclude carbobenzoxy chloride, iso-butylchloroformate,tert-butoxycarbonyl chloride, di-tert-butyl dicarbonate and the likethat are reacted with the amine in non-protic or dipolar aproticsolvents such as DMF or THF or mixtures of solvents. A preferred reagentis di-tert-butyl dicarbonate and a preferred solvent is THF.

Removal of protecting groups such as carbamates, silyl groups andbenzyl, p-methoxybenzyl, or other substituted benzyl groups ordiphenylmethyl (benzhydryl) or triphenylmethyl (trityl) can be carriedout at different stages in the synthesis of the compounds of thisinvention as required by methods selected by one skilled in the art.These methods are well known in the art including the amino acid, aminoacid coupling, peptide synthesis, peptide mimetic synthesis art.

Exemplary removal methods include catalytic hydrogenation, basehydrolysis, carbonyl addition reactions, acid hydrolysis and the like.Both the preparation and removal of protecting groups, for example,carbamates, benzyl groups and/or substitued arylalkyl groups isdiscussed in Green, T. et al., Protecting Groups in Organic Chemistry,second Ed., John Wiley & Sons, Inc., New York (1991). A preferred methodof removal of a BOC group is use of HCl gas in methylene chloride which,following normal work-up, provides directly an HCl salt of an usefulamino acid precursor.

In the case where P is hydrogen; i.e., where the intermediate is acarboxylic acid, standard coupling reactions can be used to form thecompounds of this invention including protected intermediates. Forexample, the acid can be converted into an acid chloride, mixedanhydride or activated ester and reacted with an alcohol, hydroxylamineor a protected hydroxylamine in the presence of base to form thenitrogen acylated compound. This is the same product as discussed above.Bases are discussed above and include N-methyl-morpholine, triethylamine and the like. Coupling reactions of this nature are well known inthe art and especially the art related to peptide and amino acidchemistry. Removal of the P group can be accomplished, if desired, usingstandard hydrolysis conditions such as base hydrolysis or exchange oracid exchange or hydrolysis.

Schemes 1A through 2C, hereinafter, also illustrate conversion of acarboxylic acid protected as an ester or amide into a hydroxamic acidderivative such as a O-arylalkylether or O-cycloalkoxyalkylether groupsuch as the THP group. Methods of reacting an acid or acid derivativewith hydroxylamine or a hydroxylamine derivative are discussed above.

For example, hydroxylamine can be used in an exchange reaction bytreatment of a precursor compound, where P is an ester or amide, withone or more equivalents of hydroxylamine hydrochloride or hydroxylamineat room temperature or above. This reaction can provide a hydroxamicacid directly. The solvent or solvents are usually protic or proticsolvent mixtures such as those listed above. This exchange process canbe further catalyzed by the addition of additional acid.

Alternatively, a base such as a salt of an alcohol used as a solvent,for example, sodium methoxide in methanol, can be used to formhydroxylamine from hydroxylamine hydrochloride in situ that can exchangewith an ester or amide. As mentioned above, exchange can be carried outwith a protected hydroxyl amine such as tetrahydropyranylhydroxyamine(THPONH₂), benzylhydroxylamine (BnONH₂) and the like in which case thecompounds formed are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamicacid derivatives.

Removal of the protecting groups when desired, for example, followingfurther transformations in another part of the molecule or followingstorage, can be accomplished by standard methods well known in the artsuch as acid hydrolysis of the THP group as discussed above or reductiveremoval of the benzyl group with hydrogen and a metal catalyst such aspalladium, platinum, palladium on carbon or nickel. Preferred isreaction of the hydroxybenzotriazole (HOBT) ester of an acid withhydroxylamine in water or a water/organic solvent mixture.

Sulfone compounds such as those where R¹ is nitrobenzene can be preparedas compounds of this invention by synthesis of a thiol, displacement ofan electrophile (X) by the nucleophilic thiol or thiolate and oxidationof the product thiol ether to the sulfone. For example, displacement ofthe electrophilic group X with a nitro-benzene-thiol can yield acompound where R¹ is nitrobenzene that can be reduced to provide auseful amino compound wherein Ris an aniline. It should be noted thatnitrobenzenethiol is an example and not to be considered as limiting orrequired. Oxidation of the thioether product can be carried out asdiscussed below when desired.

The reduction of nitro groups to amines is well known in the art with apreferred method being hydrogenation. There is usually a metal catalystsuch as Rh, Pd, Pt, Ni or the like with or without an additional supportsuch as carbon, barium carbonate and the like. Solvents can be protic ornon-protic pure solvents or mixed solvents as required. The reductionscan be carried out at atmospheric pressure to a pressure of multipleatmospheres with atmospheric pressure to about 40 pounds per square inch(psi) preferred.

The resulting amino group can be alkylated if desired. It can also beacylated with, for example, an aroyl chloride, heteroaryl chloride orother amine carbonyl-forming agent to form an R¹ amide of thisinnvention. The amino sulfone or thioether can also be reacted with acarbonic acid ester chloride, a sulfonyl chloride, a carbamoyl chlorideor an isocyanate to produce the corresponding carbamate, sulfonamides,or ureas of this invention.

Acylation of amines of this type are well known in the art and thereagents are also well known. Usually these reactions are carried out inaprotic solvents under an inert or/and dry atmosphere at about 45° C. toabout −10° C. An equivalent of a non-competitive base is usually usedwith sulfonyl chloride, acid chloride or carbonyl chloride reagents.Following or before this acylation step, synthesis of the hydroxamicacid products of this invention can proceed as discussed.

Other thiol reagents can also be used in the preparation of compounds ofthis invention. Examples are fluoroaryl, fluoroheteroaryl, azidoaryl orazidoheteroaryl or heteroaryl thiol reagents. These thiols can be used anucleophiles to as discused above. Oxidation to the correspondingsulfone can then be carried out after the nucleophjilic reaction iscompleted.

The fluoro-substituted sulfone resulting from such an oxidation can betreated with a nucleophile such as ammonia, a primary amine, aquaternary ammonium or metal azide salt, under pressure if desired, toprovide an azido, amino or substituted amino group that can then bereacted an activated benzoic or substituted benzoic acid derivative toform a benzamide. Azides can be reduced to an amino group using, forexample, hydrogen with a metal catalyst or metal chelate catalyst or byan activated hydride transfer reagent. The amines can be acylated asdiscussed above. Preferred methods of preparing aminethiol intermediatesof this invention include protection of an aromatic or heteroaromaticthiol with trityl chloride to form the trityl thiol derivative,treatment of the amine with as reagent such as an aromatic orheteraromatic acid chloride to form the amide, removal to the tritylgroup, with acid to form the thiol. Preferred acylating agents includebenzoyl chloride and preferred trityl remoing reagents includetriflouroacetic acid and trisiopropylsilane.

The fluorine on the fluorosulfone precursors can also be displaced withother aryl or heteroaryl nucleophiles for form compounds of thisinvention. Examples of such nucleophiles include salts of phenols,thiophenols, —OH group-containing aromatic heterocyclic compounds or —SHcontaining heteroaryl compounds. Tautomers of such groups azo, hydrazo,—OH or —SH are specifically included as useful isomers.

A preferred method of preparing intermediates in the synthesis of thesubstituted sulfones is by oxidation of an appropriate acetophenone,prepared from a flouroacetophenone, with for example, peroxymonosulfate,to form the corresponding phenol-ether. This is converted into itsdimethylthiocarbamoyl derivative using dimethylthiocarbamoyl chloride,rearranging the dimethylthiocarbamoyl derivative with heat to providethe thiol required for preparation of the thioether intermediatediscussed above and shown in the schemes.

The compounds of this invention including protected compounds orintermediates can be oxidized to the sulfones as shown in the schemesand discussed above. The selection of the stage of the alternativesynthesis to implement this conversion of sulfides into the sulfones orsulfoxides can be carried out by one skilled in the art. Reagents forthis oxidation process, in a non-limiting example, includeperoxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoicacid, perbenzoic acid, peracetic acid, perlactic acid, tert-butylperoxide, tert-butyl hydroperoxide, tert-butyl hypochlorite, sodiumhypochlorite, hypochlorous acid, sodium meta-peroiodate, periodic acid,ozone and the like. Protic, non-protic, dipolar aprotic solvents, eitherpure or mixed, can be chosen, for example, methanol/water.

The oxidation can be carried out at temperature of about −68° C. toabout 50° degrees centigrade and normally selected from a range −10° C.to about 40° C. Preparation of the sulfones can also be carried out intwo steps by the oxidation of a sulfide to a sulfoxide followed byoxidation of the sulfoxide to the sulfone. This can occur in one pot orby isolation of the sulfoxide. This latter oxidation can be carried outin a manner similar to the oxidation directly to the sulfone except thatabout one equivalent of oxidizing agent can be used, preferably at alower temperature such as about zero degrees Celsius. Preferredoxidizing agents include peroxymonosulfate and meta-chloroperbenzoicacid.

The before-discussed reactions can be carried out under a dry inertatmosphere such a nitrogen or argon if desired. Selected reactions knownto those skilled in the art can be carried out under a dry atmospheresuch as dry air whereas other synthetic steps, for example, aqueous acidor base ester or amide hydrolysis, can be carried out under laboratoryair. In addition, some processes of these syntheses can be carried outin a pressure apparatus at pressures above, equal to or belowatmospheric pressure. The use of such an apparatus aids in the controlof gaseous reagents such as hydrogen, ammonia, trimethylamine,methylamine, oxygen and the like, and can also help prevent the leakageof air or humidity into a reaction in progress. This discussion is notintended to be exhaustive as it is readily noted that additional oralternative methods, conditions, reactions or systems can be identifiedand used by a chemist of ordinary skill.

Schemes 1 and 2 that are provided hereinafter illustrate specificreactions useful in preparing a contemplated compound. Further specificsfor those reactions can be found in the Examples that follow.

The exemplary reactions are usually carried out at a temperature ofabout −25° C. to solvent reflux under an inert atmosphere such asnitrogen or argon. The solvent or solvent mixture can vary widelydepending upon reagents and other conditions and can include polar ordipolar aprotic solvents as listed or mixtures of these solvents.

In some cases, amines such as triethyl amine, pyridine or othernon-reactive bases can serve as reagents and/or solvents and/orco-solvents. In some instances, in these reactions and other reactionsin these Schemes, protecting groups can be used to maintain or retaingroups in other parts of a molecule(s) at locations that is(are) notdesired reactive centers. Examples of such groups that the skilledperson might want to maintain or retain include, amines, otherhydroxyls, thiols, acids and the like. Such protecting groups caninclude acyl groups, arylalkyl groups, carbamoyl groups, ethers,alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groupsincluding trisubstituted silyl groups, ester groups and the like.Examples of such protecting groups include acetyl, trifluoroacetyl,tetrahydropyran (THP), benzyl, tert-butoxy carbonyl (BOC or TBOC),benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) ormethoxyethoxymethylene (MEM) groups. The preparation of such protectedcompounds as well as their removal is well known in the art.

Many reactions or processes involve bases that can act as reactants,reagents, deprotonating agents, acid scavengers, salt forming reagents,solvents, co-solvents and the like. Bases that can be used include, forexample, metal hydroxides such as sodium, potassium, lithium, cesium ormagnesium hydroxide, oxides such as those of sodium, potassium, lithium,calcium or magnesium, metal carbonates such as those of sodium,potassium, lithium, cesium, calcium or magnesium, metal bicarbonatessuch as sodium bicarbonate or potassium bicarbonate, primary (I°),secondary (II°) or tertiary (III°) organic amines such as alkyl amines,arylalkyl amines, alkylarylalkyl amines, heterocyclic amines orheteroaryl amines, ammonium hydroxides or quaternary ammoniumhydroxides. As non-limiting examples, such amines can includetriethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine,diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine,N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine,1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine, diazabicyclononane and the like.Non-limiting examples of ammonium hydroxides, usually made from aminesand water, can include ammonium hydroxide, triethyl ammonium hydroxide,trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide,tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide,morpholinium hydroxide, N-methylmorpholinium hydroxide,N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, andthe like. As non-limiting examples, quaternary ammonium hydroxides caninclude tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide,dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammoniumhydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethylmorpholinium hydroxide,N,N,N′,N′-tetramethylpiperazenium hydroxide, andN-ethyl-N′-hexylpiperidinium hydroxide and the like.

Metal hydrides, amides or alcoholates such as calcium hydride, sodiumhydride, potassium hydride, lithium hydride, aluminum hydride,diisobutylaluminum hydride (DIBAL) sodium methoxide, potassiumtert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide,potassium diisopropyl amide and the like can also be suitable reagents.Organometallic deprotonating agents such as alkyl or aryl lithiumreagents such as methyl lithium, phenyl lithium, tert-butyl lithium,lithium acetylide or butyl lithium, Grignard reagents such asmethylmagnesium bromide or methymagnesium chloride, organocadiumreagents such as dimethylcadium and the like can also serve as bases forcausing salt formation or catalyzing the reaction. Quaternary ammoniumhydroxides or mixed salts are also useful for aiding phase transfercouplings or serving as phase transfer reagents. Pharmaceuticallyacceptable bases and be reacted with acids to form pharmaceuticallyacceptable salts of this invention. It should also be noted thatoptically active bases can be used to make optically active salts whichcan be used for optical resolutions.

Generally, reaction media can comprise a single solvent, mixed solventsof the same or different classes or serve as a reagent in a single ormixed solvent system. The solvents can be protic, non-protic or dipolaraprotic. Non-limiting examples of protic solvents include water,methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanoland the like. Typical non-protic solvents include acetone,tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether(TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate,methyl acetate, butyl acetate, trichloroethane, methylene chloride,ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane andthe like. Dipolar aprotic solvents include compounds such asdimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO,hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea,N-methylpyrrolidone and the like. Non-limiting examples of reagents thatcan be used as solvents or as part of a mixed solvent system includeorganic or inorganic mono- or multi-protic acids or bases such ashydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formicacid, citric acid, succinic acid, triethylamine, morpholine,N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine,potassium hydroxide, sodium hydroxide, alcohols or amines for makingesters or amides or thiols for making the products of this invention andthe like.

Salts of the compounds or intermediates of this invention are preparedin the normal manner wherein acidic compounds are reacted with basessuch as those discussed above to produce metal or nitrogen containingcation salts. Basic compounds such as amines can be treated with an acidto for form the amine salt. A preferred amine salt is the hydrochloridesalt formed by reaction of the free base with HCl or hydrochloric acid.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes well known in theart, for example by formation of diastereoisomeric salts by treatmentwith an optically active acid or base. Examples of appropriate acids aretartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers.

Still another available method involves synthesis of covalentdiastereomeric molecules, e.g., esters, amides, acetals, ketals, and thelike, by reacting compounds of Formula I with an optically active acidin an activated form, a optically active diol or an optically activeisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomericaly purecompound. In some cases, hydrolysis to the parent optically active drugis not necessary prior to dosing the patient since the compound canbehave as a prodrug. The optically active compounds of Formula I canlikewise be obtained by utilizing optically active starting materials.

In additon to the optical isomers or potential optical isomers discussedabove, other types of isomers are specifically intended to be includedin this discussion and in this invention. Examples include cis isomers,trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers,tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers,heteroatom isomers and ortho, meta or para substitution isomers are alsoincluded as isomers. Solvates or solvent addition compounds such ashydrates or alcoholates are also specifically included both as chemicalsof theis invention and in, for example, formulations or pharmaceuticalcompositions for delivery.

Contemplated equivalents of the general formulas set forth above for theMMP inhibitor compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties such as tautomers thereof and compounds wherein one or moreof the various R groups are simple variations of the substituents asdefined therein, e.g., wherein R is a higher alkyl group than thatindicated. In addition, where a substituent is designated as, or can be,a hydrogen, the exact chemical nature of a substituent which is otherthan hydrogen at that position, e.g., a hydrocarbyl radical or ahalogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure. For example, two hydroxyl groups, two amino groups,two thiol groups or a mixture of two hydrogen-heteroatom groups on thesame carbon are known not to be stable without protection or as aderivative.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions can not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

The compounds of this invention can be used in the form of salts derivedfrom inorganic or organic acids. These salts include but are not limitedto the following: acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained as desired. The salts are formed by combining the basiccompounds with the desired acid.

Other compounds of this invention that are acids can also form salts.Examples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases orbasic quaternary ammonium salt. In some cases, the salts can also beused as an aid in the isolation, purification or resolution of thecompounds.

Best Mode for Carrying Out the Invention

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limiting ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1N-Hydroxy-4-[[[4-(benzoylamino)phenyl]-sulfonyl]methyl]-4-piperidinecarboxamide,Monohydrochloride

Part A: To a solution of trityl chloride (20.24 g, 72.62 mmol) andtrifluoroacetic acid (8 mL) in dichloromethane (100 mL) was added4-aminothiophenol (10.00 g, 79.88 mmol) in dichloromethane (150 mL)dropwise. After stirring at ambient temperature for 30 minutes, thesolution was diluted with H₂O and neutralized with 2.5 N NaOH to pH=10.The organic layer was separated and washed with H₂O and dried overNa₂SO₄. The solution was concentrated in vacuo and trituration withethyl ether afforded the trityl-protected aniline compound as a tansolid (trityl 4-aminobenzenethioether; 22.85 g, 86%). HPLC purity: 98%.

Part B: To a solution of the aniline compound of Part A (10.00 g, 27.21mmol) and triethylamine (5.69 mL, 40.82 mmol) in dichloromethane (40 mL)was added benzoyl chloride (3.47 g, 29.93 mmol). After 1 hour ofstirring at ambient temperature, the mixture was diluted withdichloromethane and washed with H₂O. The organic was concentrated andafter washing with ethyl ether provided the acylated aniline compound asan off-white solid (trityl 4-[benzoylamino]benzenethioether; 13.00 g,quantitative yield). HPLC purity: 99%.

Part C: The trityl protecting group was removed from the thiol group ofthe acylated aniline of Part B as follows. To a solution of the acylatedaniline of part B (6.00 g, 12.72 mmol) in dichloromethane (25 mL) wasadded triisopropyl silane (13.03 mL, 63.61 mmoL) followed bytrifluoroacetic acid (25 mL). After 30 minutes at ambient temperaturethe mixture was concentrated in vacuo and trituration with hexaneprovided the acylated aminothiophenol as a white solid(4-[benzoylamino]benzenethiol; 3.02 g, quantitative yield).

Part D: To a solution of ethyl isonipecotate (ethyl4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL)was added a solution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound (ethyl-4-[BOC-piperidine]carboxylate; 26.2 g, quantitativeyield) as a clear, colorless oil.

Part E: To a solution of the BOC-piperidine compound of Part D (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionand stirred for 5 hours. The solution was diluted with H₂O and extractedwith ethyl ether. The organic layer was washed with H₂O, sat. NaCl, anddried over MgSO₄. Concentration provided the iodo compound (ethyl4[iodomethyl]-4-[BOC-piperidine]carboxylate; 28.8 g, quantitative yield)as a clear brown oil.

Part F: To a solution of the iodo compound of Part E (2.00 g, 5.03 mmol)in DMF (10 mL), was added K₂CO₃ (1.39 g, 10.06 mmol) followed by thethiophenol of Part C (4-[benzoylamino]benzenethiol; 1.27 g, 5.54 mmol).After stirring for 90 hours at ambient temperature, the reaction waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith H₂O and satd. NaCl and dried over Na₂SO₄. Chromatography (7:3hexane/ethyl acetate) provided the thiophenol/piperidine compound as apale yellow oil (ethyl4-[[[4-(benzoylaminophenyl]thio]methyl]-4-(BOC-piperidine)carboxylate;1.89 g, 75%). HPLC purity: 98%.

Part G: To a solution of the thiophenol/piperidine compound of Part F(1.89 g, 3.78 mmol) in ethanol (3 mL) and THF (3 mL) was added 50%aqueous NaOH (3 mL) at ambient temperature. After 18 hours the solutionwas acidified with 1N HCl to pH=2 and extracted twice with ethylacetate. The organic layers were washed with satd. NaCl and dried overNa₂SO₄. Concentration in vacuo provided the carboxylic acid compound asan orange solid(4-[[[4-(benzoylamino)phenyl]-thio]-methyl]-4-(BOC-piperidine)carboxylicacid; 1.76 g, 99%). HPLC purity: 91%.

Part H: To a solution of the carboxylic acid compound of Part G (1.74 g,3.69 mmol) in dichloromethane (20 mL) was added tetrabutylammonium-Oxone(13.10 g, 11.07 mmol). The mixture was stirred at ambient temperaturefor 18 hours. Additional tetrabutylammonium-Oxone (4.37 g, 3.69 mmol)was added to ensure complete conversion to the sulfone. After anadditional 18 hours of stirring at ambient temperature the solvent wasremoved in vacuo and the residue was dissolved into ethyl acetate. Theorganic solution was washed with H₂O, 5% aqueous KHSO₄, satd. NaCl, anddried over Na₂SO₄. Concentration in vacuo provided the sulfone compoundas a tan solid(4-[[[(benzoylamino)phenyl]sulfonyl]methyl]-4-4(BOC-piperidine)carboxylicacid; 1.88 g, quantitative yield). HPLC purity: 93%.

Part I: To a solution of the sulfone compound of Part H (0.900 g, 1.79mmol) in DMF (5 mL) was added N-hydroxybenzotriazole.H₂O (0.282 g, 2.09mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.401 g, 2.09 mmol). After 3.5 hours of stirring at ambienttemperature, 50% aqueous hydroxylamine (1.06 mL, 17.90 mmol) was added.After 2 hours the solvent was removed in vacuo and the residue wasdissolved into ethyl acetate, washed with H₂O and satd. NaCl, and driedover Na₂SO₄. Purification via reverse phase HPLC (acetonitrile/H₂O)provided the hydroxamate compound as an off-white solid(N-hydroxy-4-[[[4-(benzoylamino)phenyl]sulfonyl]methyl]-4-(BOC-piperidine)carboxamide;0.36 g, 39%). HPLC purity: 98%.

Part J: To a solution of the hydroxamate compound of Part I (0.350 g,0.675 mmol) in methanol (1 mL)/dioxane (9 mL) was added 4N HCl indioxane (10 mL) at ambient temperature. After 1 hour the solution wasconcentrated in vacuo to provide the title compound,N-hydroxy-4-[[[4-(benzoylamino)phenyl]-sulfonyl]methyl]-4-piperidinecarboxamide,monohydrochloride, as an off-white solid (0.330 g, quantitative yield).HPLC purity: 98%. HRMS calc'd for C₂₀H₂₄N₃O₅S: 418.1437, found 418.1449.

EXAMPLE 2N-Hydroxy-4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-1-(2-phenylethyl)-4-piperidinecarboxamide,Monohydrochloride

Part A: To a solution of ethyl isonipecotate (ethyl4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL)was added a solution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound (ethyl 4-[BOC-piperidine]carboxylate; 26.2 g, quantitativeyield) as a clear, colorless oil.

Part B: To a solution of the BOC-piperidine compound of Part A (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionwas complete and stirred for 5 hours. The solution was diluted with H₂Oand extracted with ethyl ether. The organic layer was washed with H₂O,satd. NaCl, and dried over MgSO₄. Concentration provided the iodocompound (ethyl-4-[iodomethyl]-4-[BOC-piperidine]carboxylate; 28.8 g,quantitative yield) as a clear brown oil.

Part C: A suspension of NaH (152 mg of a 60% dispersion in mineral oil,3.8 mmol) in DMF (3 mL) was cooled to zero degrees C. on an ice/H₂O bathand a solution of 4-(phenoxy)benzenethiol (769 mg, 3.8 mmol) in DMF (5mL) was added dropwise and stirred until a homogenous solution resulted.To this solution was added the iodo compound of Part B (1.5 g, 3.8 mmol)dropwise at zero degrees C. The solution stirred at 25° C. for 2 hours.The solution was diluted with ethyl acetate and washed with H₂O, 1NH₂SO₄, H₂O, satd. NaCl and dried over MgSO₄. Flash chromatography (15%ethyl acetate/85% hexane) on silica gel provided the sulfide compound asa clear, colorless oil (ethyl4-[[(4-phenoxyphenyl)thio]methyl]-4-(BOC-piperidine)carboxylate; 1.5 g,84%). HRMS calcd. for C₂₆H₃₃NO₅S: 471.2063, found 471.2052.

Part D: To a solution of the sulfide compound of Part C (1.47 g, 3.0mmol) in methylene chloride (60 mL) cooled to zero degrees C., was addedmeta-chloroperbenzoic acid (80%, 1.29 g, 6.0 mmol). The solution stirredfor 1.5 hours at 0° C., and was then washed with H₂O, satd. NaHCO₃, 10%Na₂SO₄, satd. NaCl, and dried over MgSO₄. Chromatography (1:4 ethylacetate/hexane) provided the sulfone compound as a white foam (ethyl4-[[(4-phenoxyphenyl)-sulfonyl]methyl]-4-(BOC-piperidine)carboxylate;920 mg, 61%).

Part E: Into a cooled solution (zero degrees C.) of the sulfone compoundof Part D (2.03 g, 4.0 mmol) in ethyl acetate (50 mL) was bubbled HClgas for 5 minutes and then stirred for 15 minutes. Concentration under astream of N₂ provided the amine hydrochloride salt as a white solid(ethyl 4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-4-piperidinecarboxylate;1.57 g, 89%).

Part F: To a suspension of the amine hydrochloride salt of part E (750mg, 1.7 mmol) in ethanol (30 mL) was added phenyl acetaldehyde (0.134mL, 1.72 mmol) followed by borane.pyridine (8M, 0.215 mL, 1.72 mmol).After 24 hours of stirring at ambient temperature, additional phenylacetaldehyde (0.134 mL) and borane.pyridine (0.215 mL) were added. Afteran additional 24 hours the ethanol was removed in vacuo followed bydilution with H₂O. The solution was extracted with dichloromethane andthe organic layer was washed with sat. NaCl and dried over MgSO₄.Chromatography (ethyl acetate/hexane) provided the benzyl compound as anoil (ethyl4-[[(4-henoxyphenyl)-sulfonyl]-methyl]-1-(2-phenylethyl)-4-piperidinecarboxylate,monohydrochloride; 690 mg, 80%). HRMS calc'd for C₂₉H₃₃NO₅S: 508.2158,found 508.2161.

Part G: To a solution of the benzyl compound of part F (680 mg, 1.3mmol) in THF (8 mL) and ethanol (8 mL) was added NaOH (520 mg, 13 mmol)in H₂O. The solution heated to 65° C. for 18 hours. The solution wasconcentrated in vacuo and the residue was dissolved in H₂O followed byacidification to pH 2. Extraction with ethyl acetate followed bytrituration with ethyl ether provided the carboxylic acid as a beigesolid(4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-1-(2-phenylethyl)-4-piperidinecarboxylicacid, monohydrochloride; 642 mg, quantitative yield). HRMS calc'd forC₂₇H₂₄NO₅S: 480.1845, found 480.1854.

Part H: To a solution of the carboxylic acid of part C (850 mg, 1.6mmol) in DMF was added N-hydroxybenzotriazole.H₂O (267 mg, 1.98 mmol)followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(429 mg, 2.24 mmol), 4-methylmorpholine (0.527 mL, 4.8 mmol) and 50%aqueous NH₂OH (1.06 mL, 16.0 mmol). The solution stirred for 18 hours atambient temperature. Additional N-hydroxybenzotriazole.H₂O (267 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (429 mg),4-methylmorpholine (0.527 mL) and 50% aqueous NH₂OH (1.06 mL) was addedand the solution stirred for 24 hours. The mixture was diluted with H₂Oand extracted with chloroform. The organic layer was washed with satd.NaCl and dried over MgSO₄. The hydrochloride salt was formed by theaddition of the free base to cold acetyl chloride in ethanol. HPLC(acetonitrile/H₂O) providedN-hydroxy-4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-1-(2-phenylethyl)-4-piperidinecarboxamide,monohydrochloride, as a white solid (460 mg, 55%). Anal. calc'd forC₂₇H₃₀N₂O₅S.0.75H₂O: C, 59.55; H, 6.02; N, 5.14. Found: C, 59.29; H,6.04; N, 5.19.

EXAMPLE 3N-Hydroxy-1-[(3-methoxyphenyl)methyl]-4-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-piperidinecarboxamide,Monohydrochloride

Part A: To a solution of ethyl isonipecotate (ethyl 4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL) was added asolution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1 mol) in THF(5 mL) dropwise over 20 minutes. The solution stirred overnight atambient temperature and concentrated in vacuo to yield a light oil. Theoil was filtered through silica gel (7:3 ethyl acetate/hexane) andconcentrated in vacuo to give the BOC-piperidine compound (ethyl4-[BOC-piperidine]carboxylate; 26.2 g, quantitative yield) as a clear,colorless oil.

Part B: To a solution of the BOC-piperidine compound of Part A (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour, diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionwas complete and stirred for 5 hours. The solution was diluted with H₂Oand extracted with ethyl ether. The organic layer is washed with H₂O,satd. NaCl and dried over MgSO₄. Concentration provided the iodocompound (ethyl 4-[iodomethyl]-4-[BOC-piperidine]carboxylate; 28.8 g,quantitative yield) as a clear brown oil.

Part C: A suspension of NaH (152 mg of a 60% dispersion in mineral oil,3.8 mmol) in DMF (3 mL) was cooled to zero degrees C. in an ice/H₂O bathand a solution of 4-(phenoxy)benzenethiol (769 mg, 3.8 mmol) in DMF (5mL) was added dropwise and stirred until a homogenous solution of sodium4-(phenoxy)benzene-thiolate resulted. To this solution was added theiodo compound of Part B (1.5 g, 3.8 mmol) dropwise at zero degrees C.The solution stirred at 25° C. for 2 hours. The solution was dilutedwith ethyl acetate and washed with H₂O, 1N H₂SO₄, H₂O, satd. NaCl anddried over MgSO₄. Flash chromatography (15% ethyl acetate/85% hexane) onsilica gel provided the sulfide compound as a clear, colorless oil(ethyl 4-[[(4-phenoxyphenyl)thio]-methyl]-4-(BOC-piperidine)carboxylate;1.5 g, 84%).

Part D: To a solution of the sulfide of Part C (1.47 g, 3.0 mmol) inmethylene chloride (60 mL) cooled to 0° C., was addedmeta-chloroperbenzoic acid (80%, 1.29 g, 6.0 mmol). The solution stirredfor 1.5 hours at 0° C., and was then washed with H₂O, satd. NaHCO₃, 10%Na₂SO₄, satd. NaCl, and dried over MgSO₄. Chromatography (1:4 ethylacetate/hexane) provided the sulfone compound as a white foam (ethyl4-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-(BOC-piperidine)carboxylate; 920mg, 61%).

Part E: Into a cooled solution (zero degrees C.) of the sulfone of PartD (1.11 g, 2.20 mmol) in ethyl acetate (30 mL) was bubbled HCl gas for 4minutes. Concentration in vacuo followed by trituration with ethyl etherprovided the amine hydrochloride salt as a white solid (ethyl4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-4-piperidinecarboxylate,monohydrochloride; 774 mg, 80%). Anal. calc'd for C₂₁H₂₅NO₅S.HCl: C,57.33; H, 5.96; N, 3.18; Cl, 8.06. Found: C, 57.29; H, 5.87; N, 3.17;Cl, 8.17.

Part F: To a solution of the amine hydrochloride salt of part E (748 mg,1.70 mmol) in methanol (7 mL) was added m-anisaldehyde (0.217 mL, 1.78mmol). After 30 minutes borane.pyridine (8M in pyridine, 0.16 mL, 0.85mmol) was added. After stirring at ambient temperature for 18 hoursadditional m-anisaldehyde (0.100 mL, 0.82 mmol) and borane.pyridine(0.106 mL, 0.85 mmol) were added and the solution stirred for 24 hours.To the mixture was added sat. NaHCO₃ and the mixture was extracted withethyl acetate. The organic layers were washed with H₂O, satd. NaCl, anddried over Na₂SO₄. Chromatography (ethyl acetate/hexane) provided the3-methoxybenzyl compound as a colorless oil (ethyl1-[3-(methoxyphenyl)methyl]-4-[[(4-phenoxyphenyl)-sulfonyl]-methyl-4-piperidinecarboxylate,monohydrochloride; 820 mg, 92%). MS(CI) MH⁺ calc'd for C₂₉H₃₃NO₆S: 524,found 524. Anal. calc'd for C₂₉H₃₃NO₆S.0.75H₂O: C, 64.84; H, 6.47; N,2.61. Found: C, 64.89; H, 6.72; N, 2.51.

Part G: To a solution of the ethyl ester of Part F (800 mg, 1.53 mmol)in ethanol (10 mL) and THF (15 mL) was added NaOH (612 mg, 15.3 mmol) inH₂O (15 mL). The solution was heated to reflux for 16 hours followed byconcentration in vacuo. Reverse phase HPLC [acetonitrile/H₂O(0.5% HCl)]provided the carboxylic acid as a yellow foam(1-[3-(methoxyphenyl)methyl]-4-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-piperidinecarboxylicacid, monohydrochloride; 891 mg, quantitative yield). HRMS calc'd forC₂₇H₂₉NO₆S: 496.1798, found 496.1794. Anal. calc'd for C₂₇H₂₉NO₆S.HCl:C, 60.95; H, 5.68; N, 2.63; Cl, 6.66. Found: C, 60.93; H, 6.02; N, 2.06;Cl, 5.84.

Part H: To a solution of the carboxylic acid compound of part G (841 mg,1.62 mmol) in DMF (6.5 mL) was added N-hydroxybenzotriazole.H₂O (263 mg,1.94 mmol) and 4-methylmorpholine (0.712 mL, 6.5 mmol) and the solutionwas cooled to zero degrees C. To this solution was added 50% aqueousNH₂OH (0.128 mL, 1.94 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (372 mg,1.94 mmol). The solution stirred for 20 hours at ambient temperature.Additional N-hydroxybenzotriazole.H₂O (263 mg), 4-methylmorpholine(0.712 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(372 mg) and 50% aqueous NH₂OH (0.128 mL) were added and the solutionstirred an additional 24 hours. After concentration under a stream of N₂the residue was dissolved in ethyl acetate and washed with sat'd NaHCO₃.Insoluble material was removed by filtration and the aqueous layer wasextracted three times with ethyl acetate. The combined organic layerswere washed with H₂O and sat'd NaCl and dried over Na₂SO₄. Followingconcentration in vacuo the residue was dissolved in ethyl acetate andHCl gas was bubbled into the solution for 15 seconds. The solution wasconcentrated under a stream of N₂. Reverse phase HPLC (acetonitrile/H₂O)providedN-hydroxy-1-[(3-methoxyphenyl)methyl]-4-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-piperidinecarboxamide, monohydrochloride as a white solid (102 mg, 11%). HPLCpurity: 93.3%. MS(EI) M⁺ calc'd for C₂₇H₃₀N₂O₆S: 511, found 511. HRMScalc'd for C₂₇H₃₀N₂O₆S: 511.1903, found 511.1907.

EXAMPLE 4N-Hydroxy-4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide,Monohydrochloride

Part A: To a solution of ethyl isonipecotate (ethyl4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL)was added a solution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound (ethyl 4-(BOC-piperidine)carboxylate; 26.2 g, quantitativeyield) as a clear, colorless oil.

Part B: To a solution of the BOC-piperidine compound of Part A (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionwas completed and stirred for 5 hours. The solution was diluted with H₂Oand extracted with ethyl ether. The organic layer was washed with H₂O,sat'd NaCl and dried over MgSO₄. Concentration provided the iodocompound (ethyl-4-[iodomethyl]-4-(BOC-piperidine)carboxylate; 28.8 g,quantitative yield) as a clear brown oil.

Part C: A suspension of NaH (152 mg as a 60% dispersion in mineral oil,3.8 mmol) in DMF (3 mL) was cooled to zero degrees C. on an ice/H₂O bathand a solution of 4-(phenoxy)benzenethiol (769 mg, 3.8 mmol) in DMF (5mL) was added dropwise and stirred until a homogenous solution of sodiumthiolate resulted. To this solution was added the iodo compound of PartB (1.5 g, 3.8 mmol) dropwise at zero degrees C. The solution stirred at25° C. for 2 hours. The solution is diluted with ethyl acetate andwashed with H₂O, 1N H₂SO₄, H₂O, sat'd NaCl, and dried over MgSO₄. Flashchromatography (15% ethyl acetate/85% hexane) on silica gel provided thesulfide compound as a clear, colorless oil (ethyl4-[[(4-phenoxyphenyl)thio]methyl]-4-(BOC-piperidine)carboxylate; 1.5 g,84%). HRMS calcd. for C₂₆H₃₃NO₅S: 471.2063, found 471.2052.

Part D: To a solution of the sulfide of Part C (1.47 g, 3.0 mmol) inmethylene chloride (60 mL) cooled to 0° C., was addedmeta-chloroperbenzoic acid (80%, 1.29 g, 6.0 mmol). The solution stirredfor 1.5 hours at 0° C., and was then washed with H₂O, satd. NaHCO₃, 10%Na₂SO₄, satd. NaCl, and dried over MgSO₄. Chromatography (1:4 ethylacetate/hexane) provided the sulfone compound as a white foam (ethyl4-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-(BOC-piperidine)carboxylate; 920mg, 61%).

Part E: Into a cooled solution (zero degrees C.) of the sulfone of PartD (2.03 g, 4.0 mmol) in ethyl acetate (50 mL) was bubbled HCl gas for 5minutes and then stirred for 15 minutes. Concentration under a stream ofN₂ provided the amine hydrochloride salt as a white solid (ethyl4-[[(4-phenoxyphenyl)sulfonyl]methyl]-4-piperidinecarboxylate,monohydrochloride; 1.57 g, 89%).

Part F: To a solution of amine hydrochloride salt of Part E (750 mg, 1.7mmol) in DMF (10 mL) was added potassium carbonate (469 mg, 3.4 mmol)followed by propargyl bromide (1-bromo-2-propyne; 80% in toluene, 253mg, 1.7 mmol) and was stirred for 5 hours. The solution was diluted withethyl acetate and washed with H₂O, satd. NaCl, and dried over MgSO₄.Purification via filtration through a silica pad (ethyl acetate)provided the propargyl amine as an oil (ethyl4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxylate,monohydrochloride; 620 mg, 82%).

Part G: To a solution of the propargyl amine of Part F (620 mg, 1.4mmol) in ethanol (5 mL) and THF (5 mL) was added NaOH (560 mg, 1.4 mmol)in 10 mL H₂O. The mixture was submerged in an oil bath at 62° C. andstirred for 18 hours. The solution was diluted with H₂O and extractedwith ethyl acetate. The aqueous was acidified to pH=4 and the resultingbeige solid was collected by vacuum filtration. Drying under high vacuumat 40° C. for 18 hours provided the carboxylic acid as a light beigesolid(4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxylicacid, monohydrochloride; 473 mg, 82%). MS(CI) MH⁺ calcd. for C₂₂H₂₃NO₅S:414, found 414. HRMS calc'd for C₂₂H₂₃NO₅S: 414.1375, found 414.1382.Anal. calc'd for C₂₂H₂₃NO₅S.HCl.0.5H₂O: C, 57.57; H, 5.49; N, 3.05; Cl,7.72; S, 6.99. Found: C, 57.59; H, 4.91; N, 2.72; Cl, 7.93; S, 6.76.

Part H: To a solution of the carboxylic acid of Part G (460 mg, 1.1mmol) in DMF (10 mL) was added N-hydroxbenzotriazole.H₂O (180 mg, 1.33mmol) and after 5 minutes of stirring was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (299 mg,1.56 mmol). After 10 additional minutes 4-methylmorpholine (0.49 mL,4.45 mmol) and 50% aqueous hydroxylamine (0.22 mL, 3.34 mmol) and thesolution stirred for 24 hours. An additional aliquot of each reagent wasadded and the solution stirred for an additional 48 hours. The solutionwas diluted with H₂O, extracted with chloroform, washed with satd. NaCland dried over MgSO₄. Reverse phase HPLC (acetonitrile/H₂O) provided thehydroxamate compound as a white solid(N-hydroxy-4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride; 200 mg, 42%). HRMS calc'd for C₂₂H₂₄N₂O₅S: 429.1489,found 429.1480. Anal. calc'd for C₂₂H₂₄N₂O₅S: C, 61.66; H, 5.64; N,6.54; S, 7.48. Found: C, 61.33; H, 5.68; N, 6.36; S, 7.35.

Part I: To a cooled (0° C.) solution of acetyl chloride (0.429 mL, 0.658mmol) in methanol (2 mL) was added the hydroxamate of part H (141 mg,0.324 mmol) in methanol (5 mL). The solution stirred for 20 minutes atzero degrees C. Concentration under a stream of N₂ followed bytrituration with ethyl ether provided(N-hydroxy-4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride as a white solid (154 mg, quantitative yield). HPLCpurity: >99%. Anal. calcd. for C₂₂H₂₄N₂O₅S.1.05HCl.0.45H₂O: C, 55.64; H,5.51; N, 5.90; Cl, 7.84. Found: C, 55.42; H, 5.63; N, 5.79; Cl, 8.02.

EXAMPLE 5 1,1-Dimethylethyl Ester4-[(Hydroxyamino)-carbonyl]-4-[[(4-phenoxyphenyl]sulfonyl]methyl]-1-piperidinecarboxylicAcid

Part A: To a solution of ethyl isonipecotate (ethyl4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL)was added a solution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound (ethyl 4-(BOC-piperidine)carboxylate; 26.2 g, quantitativeyield) as a clear, colorless oil.

Part B: To a solution of the BOC-piperidine compound of Part A (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionwas complete and stirred for 5 hours. The solution was diluted with H₂Oand extracted with ethyl ether. The organic layer is washed with H₂O,satd. NaCl and dried over MgSO₄. Concentration provided the iodocompound (ethyl 4-[iodomethyl]-4-(BOC-piperidine)carboxylate; 28.8 g,quantitative yield) as a clear brown oil.

Part C: A suspension of NaH (152 mg as a 60% dispersion in mineral oil,3.8 mmol) in DMF (3 mL) was cooled to zero degrees C. on an ice/H₂O bathand a solution of 4-(phenoxy)benzenethiol (769 mg, 3.8 mmol) in DMF (5mL) was added dropwise and stirred until a homogenous solution resulted.To this solution was added the iodo compound of Part B (1.5 g, 3.8 mmol)dropwise at zero degrees C. The solution stirred at 25° C. for 2 hours.The solution was diluted with ethyl acetate and washed with H₂O, 1NH₂SO₄, H₂O, satd. NaCl and dried over MgSO₄. Flash chromatography (15%ethyl acetate/85% hexane) on silica gel provided the sulfide compound asa clear, colorless oil (ethyl4-[[(4-phenoxyphenyl)thio]methyl]-4-(BOC-piperidine)carboxylate; 1.5 g,84%). HRMS calcd for C₂₆H₃₃NO₅S, 471.2079, found 471.2063.

Part D: To a solution of the sulfide compound of Part C (1.47 g, 3.0mmol) in methylene chloride (60 mL) cooled to zero degrees C., was addedmeta-chloroperbenzoic acid (80%, 1.29 g, 6.0 mmol). The solution stirredfor 1.5 hours at zero degrees C., and was then washed with H₂O, satd.NaHCO₃, 10% Na₂SO₄, satd. NaCl, and dried over MgSO₄. Chromatography(1:4 ethyl acetate/hexane) provided the sulfone compound as a white foam(ethyl 4-[[(4-phenoxyphenyl)sulfonyl]-methyl]1-piperidine)carboxylate920 mg, 61%).

Part E: To a solution of the sulfone compound of Part D (920 mg, 1.8mmol) in ethanol (5 mL)/THF (5 mL) was added sodium hydroxide (731 mg,1.8 mmol) in H₂O (7 mL). The solution was submerged in a oil bath at 62°C. and stirred for 24 hours. After an additional 24 hours at ambienttemperature the solution was extracted with ethyl acetate. The aqueouslayer was acidified and extracted with ethyl acetate, washed with satd.NaCl, and dried over MgSO₄. Concentration in vacuo provided thecarboxylic acid as a white solid(4-[[(4-phenoxyphenyl)sulfonyl]methyl]1-piperidine)carboxylic acid; 770mg, 89%).

Part F: To a solution of the carboxylic acid of Part E (850 mg, 1.8mmol) in DMF (7 mL) was added N-hydroxybenzotriazole.H₂O (290 mg, 2.1mmol) followed, after 5 minutes, by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg, 2.5mmol). After stirring for 2.5 hours, 4-methylmorpholine (0.59 mL, 5.4mmol) and 50% aqueous hydroxylamine (0.35 mL, 5.4 mmol) was added andthe solution stirred overnight at ambient temperature. An additionalaliquot of each of the reagents was added. After an additional 24 hoursat ambient temperature the solution was diluted with H₂O and extractedwith ethyl acetate. The combined extracts were washed with sat'd NaCland dried over MgSO₄. Reverse phase HPLC (acetonitrile/H₂O) provided1,1-dimethylethyl ester4-[hydroxyamino)-carbonyl]-4-[[(4-phenoxyphenyl)-sulfonyl]methyl]-1-piperidinecarboxylicacid as a white solid (480 mg, 55%). Anal. calc'd for C₂₄H₃₀N₂O₇S: C,58.76; H, 6.16; N, 5.71; S, 6.54. Found: C, 58.64; H, 6.24; N, 5.66; S,6.66.

EXAMPLE 6N-Hydroxy-4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-4-piperidinecarboxamide,Monohydrochloride

Part A: To a solution of ethyl isonipecotate (ethyl4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL)was added a solution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound (ethyl 4-(BOC-piperidine)carboxylate; 26.2 g, quantitativeyield) as a clear, colorless oil.

Part B: To a solution of the BOC-piperidine compound of Part A (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionwas complete and stirred for 5 hours. The solution was diluted with H₂Oand extracted with ethyl ether. The organic layer is washed with H₂O,satd. NaCl and dried over MgSO₄. Concentration provided the iodocompound (ethyl 4-[iodomethyl]-4-(BOC-piperidine)carboxylate; 28.8 g,quantitative yield) as a clear brown oil.

Part C: A suspension of NaH (152 mg of a 60% dispersion in mineral oil,3.8 mmol) in DMF (3 mL) was cooled to zero degrees C. on an ice/H₂O bathand a solution of 4-(phenoxy)benzenethiol (769 mg, 3.8 mmol) in DMF (5mL) was added dropwise and stirred until a homogenous solution of sodium4-(phenoxy)benzenethiolate resulted. To this solution was added the iodocompound of Part B (1.5 g, 3.8 mmol) dropwise at zero degrees C. Thesolution stirred at 25° C. for 2 hours. The solution was diluted withethyl acetate and washed with H₂O, 1N H₂SO₄, H₂O, satd. NaCl and driedover MgSO₄. Flash chromatography (15% ethyl acetate/85% hexane) onsilica gel provided the sulfide compound as a clear, colorless oil(ethyl 4-[[(4-phenoxyphenyl)thio]-methyl]-4-(BOC-piperidine)carboxylate;1.5 g, 84%). HRMS calc'd for C₂₆H₃₃NO₅S, 471.2079, found 471.2063.

Part D: To a solution of the sulfide of Part C (1.47 g, 3.0 mmol) inmethylene chloride (60 mL) cooled to zero degrees C., was addedmeta-chloroperbenzoic acid (80%, 1.29 g, 6.0 mmol). The solution stirredfor 1.5 hours at zero degrees C., and was then washed with H₂O, satd.NaHCO₃, 10% Na₂SO₄, satd. NaCl, and dried over MgSO₄. Chromatography(1:4 ethyl acetate/hexane) provided the sulfone compound as a white foam(ethyl4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-4-(BOC-piperidine)carboxylate;920 mg, 61%).

Part E: To a solution of the sulfone compound of Part D (920 mg, 1.8mmol) in ethanol (5 mL)/THF (5 mL) was added sodium hydroxide (731 mg,1.8 mmol) in H₂O (7 mL). The solution was submerged in a oil bath at 62°C. and stirred for 24 hours. After an additional 24 hours at ambienttemperature the solution was extracted with ethyl acetate. The aqueouslayer was acidified and extracted with ethyl acetate, washed with sat'dNaCl, and dried over MgSO₄. Concentration in vacuo provided thecarboxylic acid as a white solid(4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-4-(BOC-piperidine)carboxylicacid; 770 mg, 89%).

Part F: To a solution of the carboxylic acid of Part E (850 mg, 1.8mmol) in DMF (7 mL) was added N-hydroxybenzotriazole.H₂O (290 mg, 2.1mmol) followed, after 5 minutes, by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg, 2.5mmol). After stirring for 2.5 hours, 4-methylmorpholine (0.59 mL, 5.4mmol) and 50% aqueous hydroxylamine (0.35 mL, 5.4 mmol) was added andthe solution stirred overnight at ambient temperature. An additionalaliquot of each of the reagents was added. After an additional 24 hoursat ambient temperature the solution was diluted with H₂O and extractedwith ethyl acetate. The combined extracts were washed with sat. NaCl anddried over MgSO₄. Reverse phase HPLC (CH₃CN/H₂O) provided thehydroxamate as a white solid(N-hydroxy-4-[[(4-phenoxyphenyl)sulfonyl]-methyl]-4-(BOC-piperidine)-carboxamide;480 mg, 55%). Anal. calc'd for C₂₄H₃₀N₂O₇S: C, 58.76; H, 6.16; N, 5.71;S, 6.54. Found: C, 58.64; H, 6.24; N, 5.66; S, 6.66.

Part G: HCl gas was bubbled into a solution of the hydroxamate of part F(499 mg, 1.02 mmol) in ethyl acetate (20 mL) cooled to zero degrees C.,for 2 minutes, and was allowed to stir for 0.5 hour. Trituration withethyl ether providedN-hydroxy-4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-4-piperidinecarboxamide,monohydrochloride, as a white solid (432 mg, quantitative yield). HRMScalc'd for C₁₉H₂₂N₂O₅S: 391.1328, found 391.1349. Anal. calc'd forC₁₉H₂₂N₂O₅S.HCl.H₂O: C, 51.29; H, 5.66; N, 6.30; Cl, 7.97; S, 7.21.Found: C, 50.87; H, 5.24; N, 6.22; Cl, 8.24; S, 7.07.

EXAMPLE 7N-Hydroxy-4-[[[4-(3,4-dimethylphenoxy)phenyl]sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide,Monohydrochloride

Part A: To a solution of ethyl isonipecotate (ethyl4-piperidinecarboxylate; 15.7 g, 0.1 mol) in tetrahydrofuran (100 mL)was added a solution of di-tert-butyl dicarbonate (di-t-BOC; 21.8 g, 0.1mol) in THF (5 mL) dropwise over 20 minutes. The solution stirredovernight at ambient temperature and concentrated in vacuo to yield alight oil. The oil was filtered through silica gel (7:3 ethylacetate/hexane) and concentrated in vacuo to give the BOC-piperidinecompound (ethyl 4-(BOC-piperidine)carboxylate; 26.2 g, quantitativeyield) as a clear, colorless oil.

Part B: To a solution of the BOC-piperidine compound of Part A (17.56 g,0.068 mol) in tetrahydrofuran (100 mL) cooled to −42° C. was addedlithium diisopropylamine, 1.8M in THF (37.8 mL, 0.068 mol) dropwise tonot exceed −40° C. After 1 hour diiodomethane (5.5 mL, 0.068 mol) wasadded. The solution was warmed to ambient temperature after the additionwas complete and stirred for 5 hours. The solution was diluted with H₂Oand extracted with ethyl ether. The organic layer was washed with H₂O,satd. NaCl and dried over MgSO₄. Concentration provided the iodocompound (ethyl 4-[iodomethyl)-4-(BOC-piperidine)carboxylate; 28.8 g,quantitative yield) as a clear brown oil.

Part C: To a solution of 4-fluoroacetophenone (4-fluorophenyl methylketone; 27.63 g, 0.20 mol) and 3,4-dimethylphenol (24.43 g, 0.20 mol) indimethylacetamide (200 mL) was added K₂CO₃ (33.17 g, 0.24 mol) and themixture heated to reflux for 8 hours. After concentration of solvent theresidue was dissolved in ethyl acetate (400 mL) and H₂O (200 mL), washedwith 1N HCl (200 mL) and sat. NaCl (200 mL) and dried over Na₂SO₄.Recrystallization from hot ethyl acetate/hexanes provided theacetophenone compound as a solid (28.5 g, 59%). HPLC purity: 99%.

Part D: To a solution of the acetophenone compound of part C (26.04 g,108.4 mmol) in methanol (590 mL) and H₂O (65 mL) was added Oxone® (133g, 216.7 mmol). The mixture was heated to reflux for 5.5 hours and aftercooling to ambient temperature, the excess Oxone® was removed byfiltration and was washed with methanol. After concentration of solventthe residue was dissolved in ethyl acetate (400 mL) and washed with H₂O(300 mL) and dried over Na₂SO₄. Purification by chromatography (10%ethyl acetate/hexanes to 20% ethyl acetate/hexanes) provided the phenolcompound as a solid (13.98 g, 60%). HPLC purity: >99%. MS(CI) MH⁺ calc'dfor C₁₄H₁₄O₂: 215, found 215.

Part E: To a solution of KOH (8 g, 143 mmol) in H₂O (85 mL), cooled to0° C., was added the phenol compound of Part D (13.7 g, 64.0 mmol)followed by the dropwise addition of dimethylthiocarbamoyl chloride(10.6 g, 85.8 mmol) in THF (75 mL). The solution stirred for 4.5 hoursat zero degrees C. followed by extraction with toluene (2×125 mL). Theorganic layers were combined and dried over MgSO₄. Purification bychromatography (95:5 hexane/ethyl acetate with 1% triethylamine)provided the thiocarbamate compound as a white solid (10.9 g, 56%). HPLCpurity: >99%.

Part F: The thiocarbamate compound of Part E (10.9 g, 53.6 mmol) washeated to 290° C. for 15 minutes. The compound was cooled to ambienttemperature and dissolved into an 8:1 mixture of ethylene glycol/H₂O.Added to this solution was KOH (9.0 g, 161 mmol) and the mixture stirredfor 1.5 hours. The mixture was poured over ice (125 g) and conc. HCl (6mL) was added. The mixture was extracted with chloroform (1×100 mL) anddichloromethane (2×60 mL) and the combined organic layers were driedover MgSO₄. Purification by chromatography (hexane) provided thethiophenol as a colorless liquid (4-(3,4-dimethylphenoxy)benzenethiol;4.0 g, 32%).

Part G: A suspension of NaH (600 mg of a 60% dispersion in mineral oil,15 mmol) in DMF (10 mL) was cooled to zero degrees C. and the thiophenolcompound of part F (3.45 g, 15 mmol) in DMF (7 mL) was added dropwise togenerate the sodium thiophenolate anion. After the solution washomogeneous, the iodo compound of part B (5.96 g, 15 mmol) in DMF (10mL) was added. The solution stirred for 30 minutes at zero degrees C.and for 4 hours at ambient temperature. The reaction was quenched by theaddition of H₂O and was extracted with ethyl acetate. The combinedorganic layers were washed with satd. NaCl and dried over MgSO₄.Chromatography (ethyl acetate/hexane) provided the sulfide compound as aclear oil (ethyl4-[[[4-(3,4-dimethylphenoxy)-phenyl]-thio]-methyl]-4-(BOC-piperidine)carboxylate;6.45 g, 86%).

Part H: To a solution of the sulfide compound of part G (6.45 g, 13mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid(4.45 g, 26 mmol). The solution was stirred at zero degrees C. for 3hours. The solution was diluted with dichloromethane and washed with H₂Oand sat'd NaCl, and dried over MgSO₄. Chromatography (ethylacetate/hexane) provided the sulfone compound as a white solid (ethyl4-[[[4-(3,4-dimethylphenoxy)-phenyl]-sulfonyl]-methyl]-4-(BOC-piperidine)carboxylate;6.7 g, 98%). Anal. calc'd for C₂₈H₃₇NO₇S.H₂O: C, 61.18; H, 7.15; N,2.55; S, 5.83. Found: C, 61.32; H, 7.11; N, 2.44; S, 5.16.

Part I: Into a solution of the sulfone compound of part H (6.7 g, 13mmol) cooled to zero degrees C. was bubbled HCl gas for 15 minutes. Thesolution was concentrated in vacuo and trituration with ethyl etherprovided the amine hydrochloride salt as a white solid (ethyl4-[[[4-(3,4-dimethylphenoxy)-phenyl]-sulfonyl]-methyl]-4-piperidinecarboxylate,monohydrochloride; 5.4 g, 89%). MS(CI) MH⁺ calc'd for C₂₃H₃₀NO₅S: 432,found 432.

Part J: To a solution of the amine hydrochloride salt of part I (5.4 g,11 mmol) and K₂CO₃ (3.17 g, 23 mmol) in DMF (70 mL) was added propargylbromide (1-bromo-2-propyne; 0.98 mL, 11 mmol) and the solution stirredfor 4 hours. The solution was diluted with H₂O and extracted with ethylacetate. The organic layer was washed with satd. NaCl and dried overMgSO₄. Chromatography (ethyl acetate/hexane) provided the propargylamine compound (ethyl4-[[[4-(3,4-dimethylphenoxy)-phenyl]-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxylate,monohydrochloride; 4.28 g, 82%). HRMS calc'd for C₂₆H₃₁NO₅S: 469.1923,found 469.1908. Anal. calc'd for C26H₃₁NO₅S.0.5CH₃CH₂COOCH₃: C, 65.47;H, 6.87; N, 2.73; S, 6.24. Found: C, 65.50; H, 7.02; N, 2.66; S, 6.15.

Part K: To a solution of the propargyl amine compound of part J (4.13 g,8.79 mmol) in THF (50 ml) and ethanol (50 mL) was added NaOH (3.52 g,87.95 mmol) in H₂O (30 mL) and the solution was heated at 65° C. for 18hours. Additional NaOH (703 mg, 17.58 mmol) was added and the solutionheated at 65° C. for 18 hours. The solvent was concentrated in vacuo andthe aqueous residue was extracted with ethyl acetate. The aqueous layerwas acidified to pH 2 and extracted with ethyl acetate. Followingconcentration in vacuo the white residue was triturated with ethyl etherto provide the carboxylic acid as a white solid(4-[[4-(3,4-dimethylphenoxy)-phenyl]-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxylicacid, monohydrochloride; 3.8 g, quantitative yield). HRMS calc'd forC₂₄H₂₇NO₅S: 441.1608, found 441.1651.

Part L: To a solution of the carboxylic acid of part K (1.0 g, 2.26mmol) in dichloromethane (10 mL) was added triethylamine (0.945 mL, 6.78mmol) and 50% aqueous hydroxylamine (1.5 mL, 2.26 mmol) followed byPyBroP® (1.16 g, 2.48 mmol) and the suspension stirred for 5 hours. Theunreacted starting material was removed by filtration and the filtratewas diluted with dichloromethane and washed with satd. NaCl and driedover MgSO₄. Reverse phase chromatography provided the hydroxamate as awhite solid(N-hydroxy-4-[[[4-(3,4-dimethylphenoxy)-phenyl]-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride; 215 mg, 21%). Anal. calcd. for C₂₄H₂₈N₂O₅S: C, 63.14;H, 6.18; N, 6.14; S, 7.02. Found: C, 62.78; H, 6.06; N, 6.17; S, 6.86.

Part M: To a solution of the propargyl amine compound of part L (205 mg,0.449 mmol) in methanol (4 mL) cooled to zero degrees C. was added acooled solution of acetyl chloride (0.035 mL, 0.494 mmol) in methanol (1mL). The solution stirred for 30 minutes at ambient temperature.Concentration under a stream of N₂ followed by trituration with ethylether providedN-hydroxy-4-[[[4-(3,4-dimethylphenoxy)-phenyl]sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide,monohydrochloride, as a white solid (191 mg, 86%). MS(CI) MH⁺ calc'd forC₂₄H₂₈N₂O₅S: 457, found 457. Anal. calc'd for C₂₄H₂₈N₂O₅S.HCl.H₂O: C,57.42; H, 6.02; N, 5.58; Cl, 7.06. Found: C, 57.36; H, 6.32; N, 5.68; S,6.84.

EXAMPLE 8N-Hydroxy-2-[[(4-phenoxyphenyl)sulfonyl]-methyl]-1-(2-propynyl)-2-pyrrolidineCarboxamide, Monohydrochloride

Part A: To a solution of CBZ-proline methyl ester (2.0 g, 7.6 mmol) inTHF (10 mL) cooled to −76° C. was added lithium diisopropylamine, 1.8Min THF (4.5 mL, 8.1 mmol) and the solution was stirred for 1 hour. Tothis solution was added diiodomethane (0.67 mL, 8.3 mmol) and thesolution was stirred for 20 hours at ambient temperature. The solutionwas concentrated and the residue was dissolved into ethyl acetate andwashed with H₂O and dried over MgSO₄. Chromatography (ethylacetate/hexane) provided the iodo compound as a yellow oil (980 mg, 32%)

Part B: To a solution of 4-(phenoxy)benzenethiol (2.0 g, 9.9 mmol) inDMF (3 mL) was added NaH (60% suspension in mineral oil, 400 mg, 10mmol) and the solution stirred at zero degrees C. for 30 minutes. Thissolution was added to a solution of the iodo compound of part A (4.0 g,9.9 mmol) in DMF (4 mL) and the mixture was stirred for 18 hours atambient temperature. The solution was concentrated in vacuo and theresidue was dissolved into ethyl acetate and washed with H₂O and driedover MgSO₄. Chromatography (ethyl acetate/hexane) provided the sulfideas a yellow oil (1.9 g, 40%).

Part C: To a solution of the sulfide of part B (1.9 g, 4.0 mmol) inmethanol (300 mL) and H₂O (30 mL) was added Oxone® and the mixture wasstirred for 20 hours at ambient temperature. The excess solids werecollected by filtration and the filtrate was concentrated in vacuo. Theresidue was dissolved in ethyl acetate and washed with H₂O and driedover MgSO₄. Concentration in vacuo provided the sulfone as a yellowsolid (2.0 g, 98%).

Part D: To a solution of 10% Pd on C (410 mg, 0.38 mmol) in methanol (40mL) was added the sulfone of part C (2.0 g, 3.9 mmol) and the solutionstirred under a H₂ atmosphere for 20 hours at ambient temperature. Themixture was filtered and the filtrate was concentrated. Chromatography(ethyl acetate/hexane) provided the amine as an oil (1.0 g, 69%).

Part E: To a solution of the amine of part D (1.0 g, 2.6 mmol) in DMF(10 mL) was added K₂CO₃ (1.1 g, 7.9 mmol) and propargyl bromide (0.40mL, 5.3 mmol) and the solution stirred for 20 hours at ambienttemperature. The solution was concentrated in vacuo and the residue wasdissolved into 1M KHSO₄. The solution was extracted with ethyl ether andthe aqueous was made basic with saturated NaHCO₃. The aqueous layer wasextracted with ethyl acetate, and concentration in vacuo provided thepropargyl amine as a solid (600 mg, 51%).

Part F: To a solution of the propargyl amine of part E (500 mg, 1.1mmol) in methanol (5 mL) and THF (5 mL) was added NaOH (440 mg, 11 mmol)in H₂O (10 mL) and the solution was heated to reflux for 20 hours. Thesolution was concentrated in vacuo and the residue was dissolved intoH₂O. The solution was extracted with ethyl ether and the aqueous portionwas acidified with concentrated HCl to pH=3. The resulting whiteprecipitate was collected by filtration to provide the acid (400 mg,76%).

Part G: To a solution of the acid of part F (320 mg, 0.80 mmol) in DMF(10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (510 mg, 2.7 mmol) and N-hydroxybenzotriazole (370 mg, 2.7mmol) followed by N-methylmorpholine (0.36 mL, 3.2 mmol) and 50% aqueoushydroxylamine (0.5 mL). The solution was stirred for 20 hours at ambienttemperature. The solution was then concentrated in vacuo and the residuewas dissolved into ethyl acetate. The ethyl acetate solution was washedwith H₂O and dried over MgSO₄. After concentration in vacuo, the residuewas dissolved into acetonitrile and concentrated HCl was added to formthe HCl salt. Reverse phase chromatography (acetonitrile/H₂O) providedthe title compound as a white solid (130 mg, 36%). MS(CI) MH⁺ calcd. forC₂₁H₂₂N₂O₅S: 415, found 415. Anal. calc. for C₂₁H₂₂N₂O₅S.HCL: C, 55.93;H, 5.14; N, 6.21. Found: C, 55.76; H, 5.37; N, 5.72.

EXAMPLE 9 In vitro Metalloprotease Inhibition

The compounds prepared in the manner described in Examples 1 to 9 wereassayed for activity by an in vitro assay. Following the procedures ofKnight et al., FEBS Lett. 296(3):263 (1992). Briefly,4-aminophenylmercuric acetate (APMA) or trypsin activated MMPs wereincubated with various concentrations of the inhibitor compound at roomtemperature for 5 minutes.

More specifically, recombinant human MMP-13 and MMP-1 enzymes wereprepared in laboratories of the assignee. MMP-13 was expressed inbaculovirus as a proenzyme, and purified first over a heparin agarosecolumn and then over a chelating zinc chloride column. The proenzyme wasactivated by APMA for use in the assay. MMP-1 expressed in transfectedHT-1080 cells was provided by Dr. Howard Welgus of WashingtonUniversity, St. Louis, Mo. The enzyme was also activated using APMA andwas then purified over a hydroxamic acid column.

The enzyme substrate is a methoxycoumarin-containing polypeptide havingthe following sequence:

MCA-ProLeuGlyLeuDpaAlaArgNH₂, wherein MCA is methoxycoumarin and Dpa is3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate iscommercially available from Baychem as product M-1895.

The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mMCaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl ether at a pHvalue of 7.5. Assays were carried out at room temperature, and dimethylsulfoxide (DMSO) at a final concentration of 1 percent was used todissolve inhibitor compound.

The assayed inhibitor compound in DMSO/buffer solution was compared toan equal amount of DMSO/buffer with no inhibitor as control usingMicrofluor™ White Plates (Dynatech). The inhibitor or control solutionwas maintained in the plate for 10 minutes and the substrate was addedto provide a final concentration of 4 μM.

In the absence of inhibitor activity, a fluorogenic peptide was cleavedat the gly-leu peptide bond, separating the highly fluorogenic peptidefrom a 2,4-dinitrophenyl quencher, resulting in an increase offluorescence intensity (excitation at 328 nm/emission at 415 nm).Inhibition was measured as a reduction in fluorescent intensity as afunction of inhibitor concentration, using a Perkin Elmer L550 platereader. The IC₅₀ values were calculated from those values. The resultsare set forth in the Inhibition Table (Table 13) below, reported interms of IC₅₀ values in nanomolar (nm) amounts.

TABLE 13 Ex- ample MMP-13 MMP-1 MMP-2 MMP-3 MMP-8 MMP-9 1 243 >10,0001.8 >10,000 180 1700 2 1.1 700 0.3 42.5 3.0 9.0 3 0.4 330 0.2 18.1 0.41.1 4 0.6 485 0.3 35 0.6 4.5 5 0.2 475 0.2 6 8 2400 2.8 158 2.4 30 70.85 7700 0.9 0.7 7.0 8 1.3 400 0.2

EXAMPLE 9 In vivo Angiogenesis Assay

The study of angiogenesis depends on a reliable and reproducible modelfor the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, July1996, Vol. 37, No.8.

In this assay, uniformly sized Hydron™ pellets containing bFGF andsucralfate were prepared and surgically implanted into the stroma mousecornea adjacent to the temporal limbus. The pellets were formed bymaking a suspension of 20 μL sterile saline containing 10 μg recombinantbFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol.The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh were separated to release thepellets.

The corneal pocket was made by anesthetizing a 7 week old C57Bl/6 femalemouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length was performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket was dissected toward the temporallimbus. The pocket was extended to within 1.0 mm of the temporal limbus.A single pellet was placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet was then advanced to thetemporal end of the pocket. Antibiotic ointment was then applied to theeye.

Mice were dosed on a daily basis for the duration of the assay. Dosingof the animals was based on bioavailability and overall potency of thecompound. an exemplary dose is 50 mg/kg bid, po. Neovascularization ofthe corneal stroma begins at about day three and was permitted tocontinue under the influence of the assayed compound until day five. Atday five, the degree of angiogenic inhibition was scored by viewing theneovascular progression with a slit lamp microscope.

The mice were anesthetized and the studied eye was once again proptosed.The maximum vessel length of neovascularization, extending from thelimbal vascular plexus toward the pellet was measured. In addition, thecontiguous circumferential zone of neovascularization was measured asclock hours, where 30 degrees of arc equals one clock hour. The area ofangiogenesis was calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

The studied mice were thereafter compared to control mice and thedifference in the area of neovascularization was recorded. Acontemplated compound typically exhibits about 25 to about 80 percentinhibition, whereas the vehicle control exhibits zero percentinhibition. The results of this assay for several inhibitor compoundsare shown in Table 14, below.

TABLE 14 Example 6 80.0%

From the foregoing, it will be observed that numerous modifications andvariations can be carried out without departing from the true spirit andscope of the novel concepts of the present invention. It is to beunderstood that no limitation with respect to the specific examplepresented is intended or should be inferred. The disclosure is intendedto cover by the appended claims all such modifications as fall withinthe scope of the claims.

What is claimed is:
 1. A compound or a salt thereof, wherein: thecompound corresponds in structure to Formula II:

R² is straight or branched chain aliphatic C₁-C₈ hydrocarbyl, C₁-C₆hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, aryl C₁-C₄ hydrocarbyl,heteroaryl C₁-C₄ hydrocarbyl, wherein the heteroaryl is not pyridinyl;aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl; and R¹ isa substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl, or heteroaryl radical bonded directly to the depictedSO₂-group, wherein: the cyclohydrocarbyl, heterocyclo, aryl, orheteroaryl is itself substituted at its own 4-position when a 6-memberedring or at its own 3- or 4-position when a 5-membered ring with asubstituent selected from the group consisting of single-ringedcyclohydrocarbyl, single-ringed heterocyclo, single-ringed aryl,single-ringed heteroaryl, phenoxy, thiophenoxy, 4-thiopyridyl,phenylazo, phenylureido, nicotinamido, isonicotinamido, picolinamido,anilino, and benzamido.
 2. The compound or salt according to claim 1,wherein R¹ is a single-ringed aryl or heteroaryl that is 5- or6-membered, wherein: the aryl or heteroaryl is itself substituted at itsown 4-position when a 6-membered ring or at its own 3- or 4-positionwhen a 5-membered ring with a substituent selected from the groupconsisting of single-ringed aryl, single-ringed heteroaryl, phenoxy,thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido, and benzamido. 3.The compound or salt according to claim 1 wherein: R¹ is phenylsubstituted with R³ at the 4-position, and R³ is phenyl, phenoxy,thiophenoxy, phenylazo, benzamido, nicotinamido, isonicotinamido,picolinamido, or phenylureido.
 4. A compound or salt thereof, wherein:the compound corresponds in structure to Formula II:

R² is straight or branched chain aliphatic C₁-C₈ hydrocarbyl, C₁-C₆hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, aryl C₁-C₄ hydrocarbyl,heteroaryl C₁-C₄ hydrocarbyl, wherein the heteroaryl is not pyridinyl;aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl; R¹ isphenyl substituted with R³ at the 4-position; and R³ is phenyl, phenoxy,or thiophenoxy, wherein the phenyl, phenoxy, or thiophenoxy isoptionally substituted: at the meta- or para-position or both with amoiety that is selected from the group consisting of C₁-C₉hydrocarbyloxy, C₁-C₁₀ hydrocarbyl, di-C₁-C₉ hydrocarbylamino, carboxylC₁-C₈ hydrocarbyl, C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, and carboxamido C₁-C₈hydrocarbyl, or at the meta- and para-positions by two methyl groups orby a methylenedioxy group.
 5. A compound or salt thereof, wherein: thecompound corresponds in structure to Formula II:

R² is straight or branched chain aliphatic C₁-C₈ hydrocarbyl, C₁-C₆hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, aryl C₁-C₄ hydrocarbyl,heteroaryl C₁-C₄ hydrocarbyl, wherein the heteroaryl is not pyridinyl;aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl; R¹ isphenyl substituted with R³ at the 4-position; and R³ is benzamido,nicotinamido, anilino, isonicotinamido, picolinamido, or phenylureido,wherein: the benzamido, nicotinamido, anilino, isonicotinamido,picolinamido, or phenylureido is optionally substituted at its own meta-or para-position or both with a moiety selected from the groupconsisting of nitro, C₁-C₈ hydrocarbyl, C₁-C₇ hydrocarbyloxy, amino, andamino-C₂-C₄ hydroxyalkyl.
 6. A compound or salt thereof, wherein: thecompound or salt is characterizeable in that the compound or saltselectively inhibits in vitro human MMP-13, MMP-9, and/or MMP-2 activityover in vitro human MMP-1 activity; the compound corresponds instructure to Formula II:

R² is straight or branched chain aliphatic C₃-C₆ hydrocarbyl,t-butoxycarbonyl, phenethyl, 2-propynyl, or 3-methoxybenzyl; and R¹ is asubstituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo,aryl, or heteroaryl radical bonded directly to the depicted SO₂-group,wherein: the cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl isitself substituted at its own 4-position when a 6-membered ring or atits own 3- or 4-position when a 5-membered ring with a substituentselected from the group consisting of single-ringed cyclohydrocarbyl,single-ringed heterocyclo, single-ringed aryl, single-ringed heteroaryl,phenoxy, thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido,nicotinamido, isonicotinamido, picolinamido, anilino, and benzamido. 7.A compound or salt wherein the compound corresponds in structure to thefollowing formula:


8. A compound or salt according to claim 1, wherein the compoundcorresponds in structure to the following formula:


9. A compound or salt thereof according to claim 6, wherein the compoundcorresponds in structure to the following formula:


10. A compound or salt according to claim 1, wherein the compoundcorresponds in structure to the following formula:


11. A compound or salt thereof according to claim 6, wherein thecompound corresponds in structure to the following formula:


12. A compound or salt according to claim 4, wherein the compoundcorresponds in structure to the following formula:


13. A process for treating a pathological condition in a mammal,wherein: the pathological condition is treatable by inhibiting matrixmetalloprotease activity; the process comprises administering a matrixmetalloprotease inhibitor compound or a pharmaceutically acceptable saltthereof in an effective amount to the mammal; the compound correspondsin structure to Formula II:

R² is straight or branched chain aliphatic C₁-C₈ hydrocarbyl, C₁-C₆hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, aryl C₁-C₄ hydrocarbyl,heteroaryl C₁-C₄ hydrocarbyl, wherein the heteroaryl is not pyridinyl;aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl; and R¹ isa substituent containing a 5- or 6-membered cyclohydrocarbyl,heterocyclo, aryl, or heteroaryl radical bonded directly to the depictedSO₂-group, wherein: the cyclohydrocarbyl, heterocyclo, aryl, orheteroaryl is itself substituted at its own 4-position when a 6-memberedring or at its own 3- or 4-position when a 5-membered ring with asubstituent selected from the group consisting of single-ringedcyclohydrocarbyl, single-ringed heterocyclo, single-ringed aryl,single-ringed heteroaryl, phenoxy, thiophenoxy, 4-thiopyridyl,phenylazo, phenylureido, nicotinamido, isonicotinamido, picolinamido,anilino, and benzamido.
 14. A process according to claim 13, wherein R¹is a single-ringed aryl or heteroaryl that is 5- or 6-membered, wherein:the aryl or heteroaryl is itself substituted at its own 4-position whena 6-membered ring or at its own 3- or 4-position when a 5-membered ringwith a substituent selected from the group consisting of single-ringedaryl, single-ringed heteroaryl, phenoxy, thiophenoxy, 4-thiopyridyl,phenylazo, phenylureido, and benzamido.
 15. A process for treating apathological condition in a mammal, wherein: the pathological conditionis treatable by inhibiting matrix metalloprotease activity; the processcomprises administering a matrix metalloprotease inhibitor compound or apharmaceutically acceptable salt thereof in an effective amount to themammal; the compound corresponds in structure to Formula II:

R² is straight or branched chain aliphatic C₁-C₈ hydrocarbyl, C₁-C₆hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, aryl C₁-C₄ hydrocarbyl,heteroaryl C₁-C₄ hydrocarbyl, wherein the heteroaryl is not pyridinyl;aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl; R¹ isphenyl substituted with R³ at the 4-position; and R³ is phenyl, phenoxy,or thiophenoxy, wherein the phenyl, phenoxy, or thiophenoxy isoptionally substituted: at the meta- or para-position or both with amoiety that is selected from the group consisting of C₁-C₉hydrocarbyloxy, C₁-C₁₀ hydrocarbyl, di-C₁-C₉ hydrocarbylamino, carboxylC₁-C₈ hydrocarbyl, C₁-C₄ hydrocarbyloxy carbonyl C₁-C₄ hydrocarbyl,C₁-C₄ hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, and carboxamido C₁-C₈hydrocarbyl, or at the meta- and para-positions by two methyl groups orby a methylenedioxy group.
 16. A process for treating a pathologicalcondition in a mammal, wherein: the pathological condition is treatableby inhibiting matrix metalloprotease activity; the process comprisesadministering a matrix metalloprotease inhibitor compound or apharmaceutically acceptable salt thereof in an effective amount to themammal; the compound corresponds in structure to Formula II:

R² is straight or branched chain aliphatic C₁-C₈ hydrocarbyl, C₁-C₆hydrocarbyloxycarbonyl C₁-C₄ hydrocarbyl, aryl C₁-C₄ hydrocarbyl,heteroaryl C₁-C₄ hydrocarbyl, wherein the heteroaryl is not pyridinyl;aryloxy C₁-C₄ hydrocarbyl, or heteroaryloxy C₁-C₄ hydrocarbyl; R¹ isphenyl substituted with R³ at the 4-position; and R³ is benzamido,nicotinamido, anilino, isonicotinamido, picolinamido, or phenylureido,wherein: the benzamido, nicotinamido, anilino, isonicotinamido,picolinamido, or phenylureido is optionally substituted at its own meta-or para-position or both with a moiety selected from the groupconsisting of nitro, C₁-C₈ hydrocarbyl, C₁-C₇ hydrocarbyloxy, amino, andamino-C₂-C₄ hydroxyalkyl.
 17. A process for treating a pathologicalcondition in a mammal, wherein: the pathological condition is treatableby inhibiting matrix metalloprotease activity; the process comprisesadministering a matrix metalloprotease inhibitor compound or apharmaceutically acceptable salt thereof in an effective amount to themammal; the compound or salt is characterizeable in that the compound orsalt selectively inhibits in vitro human MMP-13, MMP-9, and/or MMP-2activity over in vitro human MMP-1 activity; the compound corresponds instructure to Formula II:

R² is straight or branched chain aliphatic C₃-C₆ hydrocarbyl,t-butoxycarbonyl, phenethyl, 2-propynyl, or 3-methoxybenzyl; and R¹ is asubstituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo,aryl, or heteroaryl radical bonded directly to the depicted SO₂-group,wherein: the cyclohydrocarbyl, heterocyclo, aryl, or heteroaryl isitself substituted at its own 4-position when a 6-membered ring or atits own 3- or 4-position when a 5-membered ring with a substituentselected from the group consisting of single-ringed cyclohydrocarbyl,single-ringed heterocyclo, single-ringed aryl, single-ringed heteroaryl,phenoxy, thiophenoxy, 4-thiopyridyl, phenylazo, phenylureido,nicotinamido, isonicotinamido, picolinamido, anilino, and benzamido. 18.A process according to claim 13, wherein: R¹ is phenyl substituted withR³ at the 4-position, and R³ is phenyl, phenoxy, thiophenoxy, phenylazo,benzamido, nicotinamido, isonicotinamido, picolinamido, or phenylureido.19. A process for treating a pathological condition in a mammal,wherein: the pathological condition is treatable by inhibiting matrixmetalloprotease activity; the process comprises administering a matrixmetalloprotease inhibitor compound or a pharmaceutically acceptable saltthereof in an effective amount to the mammal; wherein the compoundcorresponds in structure to the following formula:


20. A process according to claim 13, wherein the compound corresponds instructure to the following formula:


21. A process according to claim 13, wherein the compound corresponds instructure to the following formula:


22. A process according to claim 15, wherein the compound corresponds instructure to the following formula:


23. A process according to claim 17, wherein: the compound correspondsin structure to the following formula:


24. A process according to claim 17, wherein: the compound correspondsin structure to the following formula: